TY - JOUR T1 - Importance of Secondary Structure Data in Large Scale Protein Modeling using Low-Resolution SURPASS Method JF - Methods in Molecular Biology, in press Y1 - 2023 A1 - Aleksandra E. Badaczewska-Dawid A1 - Andrzej Koliński ER - TY - JOUR T1 - Integrative modeling of diverse protein-peptide systems using CABS-dock JF - PLoS Comput Biol. Y1 - 2023 A1 - Wojciech Pulawski A1 - Michal Kolinski A1 - Andrzej Koliński AB - The CABS model can be applied to a wide range of protein-protein and protein-peptide molecular modeling tasks, such as simulating folding pathways, predicting structures, docking, and analyzing the structural dynamics of molecular complexes. In this work, we use the CABS-dock tool in two diverse modeling tasks: 1) predicting the structures of amyloid protofilaments and 2) identifying cleavage sites in the peptide substrates of proteolytic enzymes. In the first case, simulations of the simultaneous docking of amyloidogenic peptides indicated that the CABS model can accurately predict the structures of amyloid protofilaments which have an in-register parallel architecture. Scoring based on a combination of symmetry criteria and estimated interaction energy values for bound monomers enables the identification of protofilament models that closely match their experimental structures for 5 out of 6 analyzed systems. For the second task, it has been shown that CABS-dock coarse-grained docking simulations can be used to identify the positions of cleavage sites in the peptide substrates of proteolytic enzymes. The cleavage site position was correctly identified for 12 out of 15 analyzed peptides. When combined with sequence-based methods, these docking simulations may lead to an efficient way of predicting cleavage sites in degraded proteins. The method also provides the atomic structures of enzyme-substrate complexes, which can give insights into enzyme-substrate interactions that are crucial for the design of new potent inhibitors. VL - 5;19(7) ER - TY - JOUR T1 - Molecular Dynamics Scoring of Protein–Peptide Models Derived from Coarse-Grained Docking JF - Molecules Y1 - 2021 A1 - Mateusz Zalewski A1 - Sebastian Kmiecik A1 - Michal Kolinski AB - One of the major challenges in the computational prediction of protein–peptide complexes is the scoring of predicted models. Usually, it is very difficult to find the most accurate solutions out of the vast number of sometimes very different and potentially plausible predictions. In this work, we tested the protocol for Molecular Dynamics (MD)-based scoring of protein–peptide complex models obtained from coarse-grained (CG) docking simulations. In the first step of the scoring procedure, all models generated by CABS-dock were reconstructed starting from their original C-alpha trace representations to all-atom (AA) structures. The second step included geometry optimization of the reconstructed complexes followed by model scoring based on receptor–ligand interaction energy estimated from short MD simulations in explicit water. We used two well-known AA MD force fields, CHARMM and AMBER, and a CG MARTINI force field. Scoring results for 66 different protein–peptide complexes show that the proposed MD-based scoring approach can be used to identify protein–peptide models of high accuracy. The results also indicate that the scoring accuracy may be significantly affected by the quality of the reconstructed protein receptor structures. VL - 26(11) UR - https://www.mdpi.com/1420-3049/26/11/3293 ER - TY - JOUR T1 - Protein-protein docking with large-scale backbone flexibility using coarse-grained Monte-Carlo simulations JF - International Journal of Molecular Sciences Y1 - 2021 A1 - Mateusz Kurcinski A1 - Sebastian Kmiecik A1 - Mateusz Zalewski A1 - Andrzej Koliński AB - Most of the protein–protein docking methods treat proteins as almost rigid objects. Only the side-chains flexibility is usually taken into account. The few approaches enabling docking with a flexible backbone typically work in two steps, in which the search for protein–protein orientations and structure flexibility are simulated separately. In this work, we propose a new straightforward approach for docking sampling. It consists of a single simulation step during which a protein undergoes large-scale backbone rearrangements, rotations, and translations. Simultaneously, the other protein exhibits small backbone fluctuations. Such extensive sampling was possible using the CABS coarse-grained protein model and Replica Exchange Monte Carlo dynamics at a reasonable computational cost. In our proof-of-concept simulations of 62 protein–protein complexes, we obtained acceptable quality models for a significant number of cases. VL - 22(14) UR - https://doi.org/10.3390/ijms22147341 ER - TY - JOUR T1 - Synthetic Transition from Thiourea-Based Compounds to Tetrazole Derivatives: Structure and Biological Evaluation of Synthesized New N-(Furan-2-ylmethyl)-1H-tetrazol-5-amine Derivatives JF - Molecules Y1 - 2021 A1 - Daniel Szulczyk A1 - Anna Bielenica A1 - Piotr Roszkowski A1 - Michał A. Dobrowolski A1 - Wioletta Olejarz A1 - Sebastian Kmiecik A1 - Malgorzata Podsiad A1 - Marta Struga AB - Twelve novel derivatives of N-(furan-2-ylmethyl)-1H-tetrazol-5-amine were synthesized. For obtained compound 8, its corresponding substrate single crystals were isolated and X-ray diffraction experiments were completed. In the initial stage of research, in silico structure-based pharmacological prediction was conducted. All compounds were screened for their antibacterial and antimycobacterial activities using standard and clinical strains. The cytotoxic activity was evaluated against a panel of human cancer cell lines, in contrast to normal (HaCaT) cell lines, by using the MTT method. All examined derivatives were found to be noncytotoxic against normal cell lines. Within the studied group, compound 6 showed the most promising results in antimicrobial studies. It inhibited four hospital S. epidermidis rods’ growth, when applied at the amount of 4 µg/mL. However, the most susceptible to the presence of compound 6 was S. epidermidis T 5501 851/19 clinical strain, for which the MIC value was only 2 µg/mL. Finally, a pharmacophore model was established based on lead compounds from this and our previous work. VL - 26 UR - https://www.mdpi.com/1420-3049/26/2/323 ER - TY - JOUR T1 - Computational reconstruction of atomistic protein structures from coarse-grained models JF - Computational and Structural Biotechnology Journal Y1 - 2020 A1 - Aleksandra E. Badaczewska-Dawid A1 - Andrzej Koliński A1 - Sebastian Kmiecik KW - coarse-grained modeling KW - protein modeling KW - protein reconstruction KW - structure prediction KW - structure refinement AB - Three-dimensional protein structures, whether determined experimentally or theoretically, are often too low resolution. In this mini-review, we outline the computational methods for protein structure reconstruction from incomplete coarse-grained to all atomistic models. Typical reconstruction schemes can be divided into four major steps. Usually, the first step is reconstruction of the protein backbone chain starting from the C-alpha trace. This is followed by side-chains rebuilding based on protein backbone geometry. Subsequently, hydrogen atoms can be reconstructed. Finally, the resulting all-atom models may require structure optimization. Many methods are available to perform each of these tasks. We discuss the available tools and their potential applications in integrative modeling pipelines that can transfer coarse-grained information from computational predictions, or experiment, to all atomistic structures. VL - 18 UR - http://www.sciencedirect.com/science/article/pii/S2001037019305537 ER - TY - JOUR T1 - Docking interactions determine early cleavage events in insulin proteolysis by pepsin: Experiment and simulation JF - International Journal of Biological Macromolecules Y1 - 2020 A1 - Michał Koliński A1 - Sebastian Kmiecik A1 - Robert Dec A1 - Marcin Piejko A1 - Paweł Mak A1 - Wojciech Dzwolak KW - Cleavage site prediction KW - Insulin KW - Pepsin KW - Peptide docking KW - Protein degradation pathways KW - Proteolysis AB - In silico modelling of cascade enzymatic proteolysis is an exceedingly complex and challenging task. Here, we study partial proteolysis of insulin by pepsin: a process leading to the release of a highly amyloidogenic two chain ‘H-fragment’. The H-fragment retains several cleavage sites for pepsin. However, under favorable conditions H-monomers rapidly self-assemble into proteolysis-resistant amyloid fibrils whose composition provides snapshots of early and intermediate stages of the proteolysis. In this work, we report a remarkable agreement of experimentally determined and simulation-predicted cleavage sites on different stages of the proteolysis. Prediction of cleavage sites was based on the comprehensive analysis of the docking interactions from direct simulation of coupled folding and binding of insulin (or its cleaved derivatives) to pepsin. The most frequent interactions were found to be between the pepsin's active site, or its direct vicinity, and the experimentally determined insulin cleavage sites, which suggest that the docking interactions govern the proteolytic process. VL - 149 UR - https://www.sciencedirect.com/science/article/pii/S0141813019401906 ER - TY - JOUR T1 - Docking of peptides to GPCRs using a combination of CABS-dock with FlexPepDock refinement JF - Briefings in Bioinformatics Y1 - 2020 A1 - Aleksandra E. Badaczewska-Dawid A1 - Sebastian Kmiecik A1 - Michal Kolinski AB - The structural description of peptide ligands bound to G protein-coupled receptors (GPCRs) is important for the discovery of new drugs and deeper understanding of the molecular mechanisms of life. Here we describe a three-stage protocol for the molecular docking of peptides to GPCRs using a set of different programs: (1) CABS-dock for docking fully flexible peptides; (2) PD2 method for the reconstruction of atomistic structures from C-alpha traces provided by CABS-dock and (3) Rosetta FlexPepDock for the refinement of protein–peptide complex structures and model scoring. We evaluated the proposed protocol on the set of seven different GPCR–peptide complexes (including one containing a cyclic peptide), for which crystallographic structures are available. We show that CABS-dock produces high resolution models in the sets of top-scored models. These sets of models, after reconstruction to all-atom representation, can be further improved by Rosetta high-resolution refinement and/or minimization, leading in most of the cases to sub-Angstrom accuracy in terms of interface root-mean-square-deviation measure. UR - https://doi.org/10.1093/bib/bbaa109 ER - TY - JOUR T1 - Flexible docking of peptides to proteins using CABS-dock JF - Protein Science, 29:211-222 Y1 - 2020 A1 - Mateusz Kurcinski A1 - Aleksandra E. Badaczewska-Dawid A1 - Michal Kolinski A1 - Andrzej Koliński A1 - Sebastian Kmiecik KW - molecular modeling KW - peptide drugs KW - peptide therapeutics KW - protein–peptide complex KW - protein–peptide interactions KW - structure prediction AB - Molecular docking of peptides to proteins can be a useful tool in the exploration of the possible peptide binding sites and poses. CABS-dock is a method for protein–peptide docking that features significant conformational flexibility of both the peptide and the protein molecules during the peptide search for a binding site. The CABS-dock has been made available as a web server and a standalone package. The web server is an easy to use tool with a simple web interface. The standalone package is a command-line program dedicated to professional users. It offers a number of advanced features, analysis tools and support for large-sized systems. In this article, we outline the current status of the CABS-dock method, its recent developments, applications, and challenges ahead. UR - https://onlinelibrary.wiley.com/doi/abs/10.1002/pro.3771 ER - TY - JOUR T1 - Isoxazole-containing 5′ mRNA cap analogues as inhibitors of the translation initiation process JF - Bioorganic Chemistry Y1 - 2020 A1 - Karolina Piecyk A1 - Maciej Lukaszewicz A1 - Karol Kamel A1 - Maria Janowska A1 - Paulina Pietrow A1 - Sebastian Kmiecik A1 - Marzena Jankowska-Anyszka KW - Cap analogue KW - Cycloaddition reaction KW - Isoxazol KW - mRNA KW - Translation initiation AB - Herein we describe a synthesis of new isoxazole-containing 5′ mRNA cap analogues via a cycloaddition reaction. The obtained analogues show a capability to inhibit cap-dependent translation in vitro and are characterized by a new binding mode in which an isoxazolic ring, instead of guanine, is involved in the stacking effect. Our study provides valuable information toward designing new compounds that can be potentially used as anticancer therapeutics. VL - 96 UR - https://www.sciencedirect.com/science/article/pii/S004520681931819X ER - TY - JOUR T1 - Phosphorylation of the N-terminal domain of ribosomal P-stalk protein uL10 governs its association with the ribosome JF - FEBS Letters Y1 - 2020 A1 - Kamil Filipek A1 - Barbara Michalec-Wawiórka A1 - Aleksandra Boguszewska A1 - Sebastian Kmiecik A1 - Marek Tchórzewski KW - GTPase-associated center KW - ribosomal protein KW - ribosomal stalk KW - ribosome KW - translation AB - The uL10 protein is the main constituent of the ribosomal P-stalk, anchoring the whole stalk to the ribosome through interactions with rRNA. The P-stalk is the core of the GTPase-associated center (GAC), a critical element for ribosome biogenesis and ribosome translational activity. All P-stalk proteins (uL10, P1, and P2) undergo phosphorylation within their C termini. Here, we show that uL10 has multiple phosphorylation sites, mapped also within the N-terminal rRNA-binding domain. Our results reveal that the introduction of a negative charge within the N terminus of uL10 impairs its association with the ribosome. These findings demonstrate that uL10 N-terminal phosphorylation has regulatory potential governing the uL10 interaction with the ribosome and may control the activity of GAC. VL - 594 UR - https://febs.onlinelibrary.wiley.com/doi/abs/10.1002/1873-3468.13885 ER - TY - CHAP T1 - Protocols for All-Atom Reconstruction and High-Resolution Refinement of Protein–Peptide Complex Structures T2 - Protein Structure Prediction Y1 - 2020 A1 - Aleksandra E. Badaczewska-Dawid A1 - Alisa Khramushin A1 - Andrzej Koliński A1 - Ora Schueler-Furman A1 - Sebastian Kmiecik AB - Structural characterizations of protein–peptide complexes may require further improvements. These may include reconstruction of missing atoms and/or structure optimization leading to higher accuracy models. In this work, we describe a workflow that generates accurate structural models of peptide–protein complexes starting from protein–peptide models in C-alpha representation generated using CABS-dock molecular docking. First, protein–peptide models are reconstructed from their C-alpha traces to all-atom representation using MODELLER. Next, they are refined using Rosetta FlexPepDock. The described workflow allows for reliable all-atom reconstruction of CABS-dock models and their further improvement to high-resolution models. JF - Protein Structure Prediction PB - Springer US CY - New York, NY SN - 978-1-0716-0708-4 UR - https://doi.org/10.1007/978-1-0716-0708-4_16 ER - TY - CHAP T1 - Protocols for Fast Simulations of Protein Structure Flexibility Using CABS-Flex and SURPASS T2 - Protein Structure Prediction Y1 - 2020 A1 - Aleksandra E. Badaczewska-Dawid A1 - Andrzej Koliński A1 - Sebastian Kmiecik AB - Conformational flexibility of protein structures can play an important role in protein function. The flexibility is often studied using computational methods since experimental characterization can be difficult. Depending on protein system size, computational tools may require large computational resources or significant simplifications in the modeled systems to speed up calculations. In this work, we present the protocols for efficient simulations of flexibility of folded protein structures that use coarse-grained simulation tools of different resolutions: medium, represented by CABS-flex, and low, represented by SUPRASS. We test the protocols using a set of 140 globular proteins and compare the results with structure fluctuations observed in MD simulations, ENM modeling, and NMR ensembles. As demonstrated, CABS-flex predictions show high correlation to experimental and MD simulation data, while SURPASS is less accurate but promising in terms of future developments. JF - Protein Structure Prediction PB - Springer US CY - New York, NY SN - 978-1-0716-0708-4 UR - https://doi.org/10.1007/978-1-0716-0708-4_20 ER - TY - JOUR T1 - Aggrescan3D (A3D) 2.0: prediction and engineering of protein solubility JF - Nucleic Acids Research Y1 - 2019 A1 - Aleksander Kuriata A1 - Valentin Iglesias A1 - Jordi Pujols A1 - Mateusz Kurcinski A1 - Sebastian Kmiecik A1 - Salvador Ventura AB - Protein aggregation is a hallmark of a growing number of human disorders and constitutes a major bottleneck in the manufacturing of therapeutic proteins. Therefore, there is a strong need of in-silico methods that can anticipate the aggregative properties of protein variants linked to disease and assist the engineering of soluble protein-based drugs. A few years ago, we developed a method for structure-based prediction of aggregation properties that takes into account the dynamic fluctuations of proteins. The method has been made available as the Aggrescan3D (A3D) web server and applied in numerous studies of protein structure-aggregation relationship. Here, we present a major update of the A3D web server to version 2.0. The new features include: extension of dynamic calculations to significantly larger and multimeric proteins, simultaneous prediction of changes in protein solubility and stability upon mutation, rapid screening for functional protein variants with improved solubility, a REST-ful service to incorporate A3D calculations in automatic pipelines, and a new, enhanced web server interface. A3D 2.0 is freely available at: http://biocomp.chem.uw.edu.pl/A3D2/ VL - 47 UR - https://doi.org/10.1093/nar/gkz321 ER - TY - JOUR T1 - Aggrescan3D standalone package for structure-based prediction of protein aggregation properties JF - Bioinformatics Y1 - 2019 A1 - Aleksander Kuriata A1 - Valentin Iglesias A1 - Mateusz Kurcinski A1 - Salvador Ventura A1 - Sebastian Kmiecik AB - SUMMARY: Aggrescan3D (A3D) standalone is a multiplatform Python package for structure-based prediction of protein aggregation properties and rational design of protein solubility. A3D allows the redesign of protein solubility by combining structural aggregation propensity and stability predictions, as demonstrated by a recent experimental study. It also enables predicting the impact of protein conformational fluctuations on the aggregation properties. The standalone A3D version is an upgrade of the original web server implementation - it introduces a number of customizable options, automated analysis of multiple mutations and offers a flexible computational framework for merging it with other computational tools. AVAILABILITY: A3D standalone is distributed under the MIT license, which is free for academic and non-profit users. It is implemented in Python. The A3D standalone source code, wiki with documentation and examples of use, and installation instructions for Linux, macOS, and Windows are available in the A3D standalone repository at https://bitbucket.org/lcbio/aggrescan3d. VL - btz143 UR - http://www.ncbi.nlm.nih.gov/pubmed/30825368 ER - TY - JOUR T1 - CABS-dock standalone: a toolbox for flexible protein-peptide docking JF - Bioinformatics Y1 - 2019 A1 - Maciej Ciemny A1 - Tymoteusz Oleniecki A1 - Aleksander Kuriata A1 - Mateusz Kurcinski A1 - Aleksandra E. Badaczewska-Dawid A1 - Andrzej Koliński A1 - Sebastian Kmiecik AB - CABS-dock standalone is a multiplatform Python package for protein-peptide docking with backbone flexibility. The main feature of the CABS-dock method is its ability to simulate significant backbone flexibility of the entire protein-peptide system in a reasonable computational time. In the default mode, the package runs a simulation of fully flexible peptide searching for a binding site on the surface of a flexible protein receptor. The flexibility level of the molecules may be defined by the user. Furthermore, the CABS-dock standalone application provides users with full control over the docking simulation from the initial setup to the analysis of results. The standalone version is an upgrade of the original web server implementation – it introduces a number of customizable options, provides support for large-sized systems and offers a framework for deeper analysis of docking results.CABS-dock standalone is distributed under the MIT license, which is free for academic and non-profit users. It is implemented in Python and Fortran. The CABS-dock standalone source code, wiki with documentation and examples of use, and installation instructions for Linux, macOS, and Windows are available in the CABS-dock standalone repository at https://bitbucket.org/lcbio/cabsdock VL - btz185 UR - https://dx.doi.org/10.1093/bioinformatics/btz185 ER - TY - CHAP T1 - Explicit-Solvent All-Atom Molecular Dynamics of Peptide Aggregation T2 - Computational Methods to Study the Structure and Dynamics of Biomolecules and Biomolecular Processes: From Bioinformatics to Molecular Quantum Mechanics Y1 - 2019 A1 - Maksim Kouza A1 - Andrzej Koliński A1 - Irina Buhimschi A1 - Andrzej Kloczkowski AB - Recent advances in computational technology have allowed us to simulate biomolecular processes on timescales that begin to reach the rates of peptide aggregation phenomena. Molecular dynamics simulations have evolved into a mature technique to the extent that they can be employed as a highly productive tool to gain meaningful insights into the structure, dynamics and molecular mechanisms of protein aggregation. In this chapter, we describe the basics of explicit solvent all-atom molecular dynamics simulations and its applications for studying early stages of aggregation processes of two short pentapeptides: KLVFF and FVFLM, related to Alzheimer's disease and preeclampsia, respectively. We focus on certain important problems in the field of protein aggregation that explicit solvent all-atom molecular dynamics simulation studies could resolve. This includes how fibril formation rates depend on a number of factors such as the presence of short peptides and population of fibril-prone conformations. Specific applications of atomistic simulations in explicit solvent to address these two issues are discussed. JF - Computational Methods to Study the Structure and Dynamics of Biomolecules and Biomolecular Processes: From Bioinformatics to Molecular Quantum Mechanics PB - Springer International Publishing SN - 978-3-319-95843-9 UR - https://doi.org/10.1007/978-3-319-95843-9_16 ER - TY - JOUR T1 - Modeling of Disordered Protein Structures Using Monte Carlo Simulations and Knowledge-Based Statistical Force Fields JF - International Journal of Molecular Sciences Y1 - 2019 A1 - Maciej Ciemny A1 - Aleksandra E. Badaczewska-Dawid A1 - Monika Pikuzinska A1 - Andrzej Koliński A1 - Sebastian Kmiecik KW - CABS model MC simulations coarse-grained disordered protein protein structure statistical force fields AB - The description of protein disordered states is important for understanding protein folding mechanisms and their functions. In this short review, we briefly describe a simulation approach to modeling protein interactions, which involve disordered peptide partners or intrinsically disordered protein regions, and unfolded states of globular proteins. It is based on the CABS coarse-grained protein model that uses a Monte Carlo (MC) sampling scheme and a knowledge-based statistical force field. We review several case studies showing that description of protein disordered states resulting from CABS simulations is consistent with experimental data. The case studies comprise investigations of protein(-)peptide binding and protein folding processes. The CABS model has been recently made available as the simulation engine of multiscale modeling tools enabling studies of protein(-)peptide docking and protein flexibility. Those tools offer customization of the modeling process, driving the conformational search using distance restraints, reconstruction of selected models to all-atom resolution, and simulation of large protein systems in a reasonable computational time. Therefore, CABS can be combined in integrative modeling pipelines incorporating experimental data and other modeling tools of various resolution. VL - 20 UR - http://www.ncbi.nlm.nih.gov/pubmed/30708941 ER - TY - CHAP T1 - Protein Dynamics Simulations Using Coarse-Grained Models T2 - Computational Methods to Study the Structure and Dynamics of Biomolecules and Biomolecular Processes: From Bioinformatics to Molecular Quantum Mechanics Y1 - 2019 A1 - Sebastian Kmiecik A1 - Jacek Wabik A1 - Michal Kolinski A1 - Maksim Kouza A1 - Andrzej Koliński AB - Simulations of protein dynamics may work on different levels of molecular detail. The levels of simplification (coarse-graining) may concern different simulation aspects, including protein representation, interaction schemes or models of molecular motion. So-called coarse-grained (CG) models offer many advantages, unreachable by classical simulation tools, as demonstrated in numerous studies of protein dynamics. Followed by a brief introduction, we present example applications of CG models for efficient predictions of biophysical mechanisms. We discuss the following topics: mechanisms of chaperonin action, mechanical properties of proteins and their complexes, membrane proteinsMembrane proteins and lipids, protein-protein interactions and intrinsically unfolded proteins. These areas illustrate the opportunities for practical applications of CG simulations. JF - Computational Methods to Study the Structure and Dynamics of Biomolecules and Biomolecular Processes: From Bioinformatics to Molecular Quantum Mechanics PB - Springer International Publishing SN - 978-3-319-95843-9 UR - https://doi.org/10.1007/978-3-319-95843-9_3 ER - TY - CHAP T1 - Protein Structure Prediction Using Coarse-Grained Models T2 - Computational Methods to Study the Structure and Dynamics of Biomolecules and Biomolecular Processes: From Bioinformatics to Molecular Quantum Mechanics Y1 - 2019 A1 - Maciej Blaszczyk A1 - Dominik Gront A1 - Sebastian Kmiecik A1 - Mateusz Kurcinski A1 - Michal Kolinski A1 - Maciej Ciemny A1 - Katarzyna Ziolkowska A1 - Marta Panek A1 - Andrzej Koliński AB - The knowledge of the three-dimensional structure of proteins is crucial for understanding many important biological processes. Most of the biologically relevant protein systems are too large for classical, atomistic molecular modeling tools. In such cases, coarse-grained (CG) models offer various opportunities for efficient conformational sampling and thus prediction of the three-dimensional structure. A variety of CG models have been proposed, each based on a similar framework consisting of a set of conceptual components such as protein representation, force field, sampling, etc. In this chapter we discuss these components, highlighting ideas which have proven to be the most successful. As CG methods are usually part of multistage procedures, we also describe approaches used for the incorporation of homology data and all-atom reconstruction methods. JF - Computational Methods to Study the Structure and Dynamics of Biomolecules and Biomolecular Processes: From Bioinformatics to Molecular Quantum Mechanics PB - Springer International Publishing SN - 978-3-319-95843-9 UR - https://doi.org/10.1007/978-3-319-95843-9_2 ER - TY - JOUR T1 - CABS-flex 2.0: a web server for fast simulations of flexibility of protein structures JF - Nucleic Acids Research, gky356 Y1 - 2018 A1 - Aleksander Kuriata A1 - Aleksandra Maria Gierut A1 - Tymoteusz Oleniecki A1 - Maciej Ciemny A1 - Andrzej Koliński A1 - Mateusz Kurcinski A1 - Sebastian Kmiecik AB - Classical simulations of protein flexibility remain computationally expensive, especially for large proteins. A few years ago, we developed a fast method for predicting protein structure fluctuations that uses a single protein model as the input. The method has been made available as the CABS-flex web server and applied in numerous studies of protein structure-function relationships. Here, we present a major update of the CABS-flex web server to version 2.0. The new features include: extension of the method to significantly larger and multimeric proteins, customizable distance restraints and simulation parameters, contact maps and a new, enhanced web server interface. CABS-flex 2.0 is freely available at http://biocomp.chem.uw.edu.pl/CABSflex2 ER - TY - JOUR T1 - CABS-flex standalone: a simulation environment for fast modeling of protein flexibility JF - Bioinformatics Y1 - 2018 A1 - Mateusz Kurcinski A1 - Tymoteusz Oleniecki A1 - Maciej Ciemny A1 - Aleksander Kuriata A1 - Andrzej Koliński A1 - Sebastian Kmiecik AB - Summary: CABS-flex standalone is a Python package for fast simulations of protein structure flexibility. The package combines simulations of protein dynamics using CABS coarse-grained protein model with the reconstruction of selected models to all-atom representation and analysis of modeling results. CABS-flex standalone is designed to allow for command-line access to the CABS computations and complete control over simulation process. CABS-flex standalone is equipped with features such as: modeling of multimeric and large-size protein systems, contact map visualizations, analysis of similarities to the reference structure and configurable modeling protocol. For instance, the user may modify the simulation parameters, distance restraints, structural clustering scheme or all-atom reconstruction parameters. With these features CABS-flex standalone can be easily incorporated into other methodologies of structural biology. Availability and implementation: CABS-flex standalone is distributed under the MIT license, which is free for academic and non-profit users. It is implemented in Python. CABS-flex source code, wiki with examples of use and installation instructions for Linux, macOS and Windows are available from the CABS-flex standalone repository at https://bitbucket.org/lcbio/cabsflex UR - http://dx.doi.org/10.1093/bioinformatics/bty685 ER - TY - JOUR T1 - Coarse-Grained Modeling of the Interplay between Secondary Structure Propensities and Protein Fold Assembly JF - Journal of Chemical Theory and Computation Y1 - 2018 A1 - Aleksandra Dawid A1 - Dominik Gront A1 - Andrzej Koliński AB -

We recently developed a new coarse-grained model of protein structure and dynamics [Dawid et al. J. Chem. Theory Comput. 2017, 13(11), 5766−5779]. The model assumed a single bead representation of amino acid residues, where positions of such united residues were defined by centers of mass of four amino acid fragments. Replica exchange Monte Carlo sampling of the model chains provided good pictures of modeled structures and their dynamics. In its generic form the statistical knowledge-based force field of the model has been dedicated for single-domain globular proteins. Sequence-specific interactions are defined by three-letter secondary structure data. In the present work we demonstrate that different assignments and/or predictions of secondary structures are usually sufficient for enforcing cooperative formation of native-like folds of SURPASS chains for the majority of single-domain globular proteins. Simulations of native-like structure assembly for a representative set of globular proteins have shown that the accuracy of secondary structure data is usually not crucial for model performance, although some specific errors can strongly distort the obtained three-dimensional structures.

VL - 14 (4) UR - https://pubs.acs.org/doi/10.1021/acs.jctc.7b01242 ER - TY - JOUR T1 - Combining Structural Aggregation Propensity and Stability Predictions To Redesign Protein Solubility JF - Molecular Pharmaceutics Y1 - 2018 A1 - Marcos Gil-Garcia A1 - Manuel Bañó-Polo A1 - Nathalia Varejão A1 - Michal Jamroz A1 - Aleksander Kuriata A1 - Marta Díaz-Caballero A1 - Jara Lascorz A1 - Bertrand Morel A1 - Susanna Navarro A1 - David Reverter A1 - Sebastian Kmiecik A1 - Salvador Ventura AB - The aggregation propensity of each particular protein seems to be shaped by evolution according to its natural abundance in the cell. The production and downstream processing of recombinant polypeptides implies attaining concentrations that are orders of magnitude above their natural levels, often resulting in their aggregation; a phenomenon that precludes the marketing of many globular proteins for biomedical or biotechnological applications. Therefore, there is a huge interest in methods aimed to increase the proteins solubility above their natural limits. Here, we demonstrate that an updated version of our AGGRESCAN 3D structural aggregation predictor, that now takes into account protein stability, allows for designing mutations at specific positions in the structure that improve the solubility of proteins without compromising their conformation. Using this approach, we have designed a highly soluble variant of the green fluorescent protein and a human single-domain VH antibody displaying significantly reduced aggregation propensity. Overall, our data indicate that the solubility of unrelated proteins can be easily tuned by in silico-designed nondestabilizing amino acid changes at their surfaces. VL - 15 UR - https://doi.org/10.1021/acs.molpharmaceut.8b00341 ER - TY - JOUR T1 - Design and synthesis of novel 1H-tetrazol-5-amine based potent antimicrobial agents: DNA topoisomerase IV and gyrase affinity evaluation supported by molecular docking studies JF - European Journal of Medicinal Chemistry Y1 - 2018 A1 - Daniel Szulczyk A1 - Michał A. Dobrowolski A1 - Piotr Roszkowski A1 - Anna Bielenica A1 - Joanna Stefańska A1 - Michal Kolinski A1 - Sebastian Kmiecik A1 - Michał Jóźwiak A1 - Małgorzata Wrzosek A1 - Wioletta Olejarz A1 - Marta Struga KW - 1H-tetrazol-5-amine KW - Antimicrobial activity KW - Cytotoxicity KW - DNA gyrase KW - molecular docking KW - Topoisomerase type IV AB - A total of 14 of 1,5-disubstituted tetrazole derivatives were prepared by reacting appropriate thiourea and sodium azide in the presence of mercury (II) chloride and triethylamine. All compounds were evaluated in vitro for their antimicrobial activity. Derivatives 10 and 11 showed the highest inhibition against Gram-positive and Gram-negative strains (standard and hospital strains). The observed minimal inhibitory concentrations values were in the range of 1–208 μM (0.25–64 μg/ml). Inhibitory activity of 1,5-tetrazole derivatives 10 and 11 against gyrase and topoisomerase IV isolated from S. aureus was studied. Evaluation was supported by molecular docking studies for all synthesized derivatives and reference ciprofloxacin. Moreover, selected tetrazoles (2, 3, 5, 6, 8, 9, 10 and 11) were evaluated for their cytotoxicity. All tested compounds are non-cytotoxic against HaCaT and A549 cells (CC50 ≤ 60 μM). VL - 156 UR - http://www.sciencedirect.com/science/article/pii/S022352341830597X ER - TY - JOUR T1 - In silico analysis of cytochrome P450 monooxygenases in chronic granulomatous infectious fungus Sporothrix schenckii: Special focus on CYP51. JF - Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics Y1 - 2018 A1 - Retshedisitswe Godfrey Matowane A1 - Lukasz Wieteska A1 - Hans Denis Bamal A1 - Ipeleng Kopano Rosinah Kgosiemang A1 - MariVan Wyk A1 - Nessie Agnes Manume A1 - Sara Mohamed Hasaan Abdalla A1 - Samson Sitheni Mashele A1 - Dominik Gront A1 - Khajamohiddin Syed KW - Docking; Genome data mining; Homology modeling; Mutations; P450; P450 diversity percentage AB - Sporotrichosis is an emerging chronic, granulomatous, subcutaneous, mycotic infection caused by Sporothrix species. Sporotrichosis is treated with the azole drug itraconazole as ketoconazole is ineffective. It is a well-known fact that azole drugs act by inhibiting cytochrome P450 monooxygenases (P450s), heme-thiolate proteins. To date, nothing is known about P450s in Sporothrix schenckii and the molecular basis of its resistance to ketoconazole. Here we present genome-wide identification, annotation, phylogenetic analysis and comprehensive P450 family-level comparative analysis of S. schenckii P450s with pathogenic fungi P450s, along with a rationale for ketoconazole resistance by S. schenckii based on in silico structural analysis of CYP51. Genome data-mining of S. schenckii revealed 40 P450s in its genome that can be grouped into 32 P450 families and 39 P450 subfamilies. Comprehensive comparative analysis of P450s revealed that S. schenckii shares 11 P450 families with plant pathogenic fungi and has three unique P450 families: CYP5077, CYP5386 and CYP5696 (novel family). Among P450s, CYP51, the main target of azole drugs was also found in S. schenckii. 3D modeling of S. schenckii CYP51 revealed the presence of characteristic P450 motifs with exceptionally large reductase interaction site 2. In silico analysis revealed number of mutations that can be associated with ketoconazole resistance, especially at the channel entrance to the active site. One of possible reason for better stabilization of itraconazole, compared to ketoconazole, is that the more extended molecule of itraconazole may form a hydrogen bond with ASN-230. This in turn may explain its effectiveness against S. schenckii vis-a-vis resistant to ketoconazole. This article is part of a Special Issue entitled: Cytochrome P450 biodiversity and biotechnology, edited by Erika Plettner, Gianfranco Gilardi, Luet Wong, Vlada Urlacher, Jared Goldstone. VL - 1866(1) UR - https://www.sciencedirect.com/science/article/pii/S1570963917302418?via%3Dihub IS - 1 ER - TY - JOUR T1 - Kinetics and mechanical stability of the fibril state control fibril formation time of polypeptide chains: A computational study JF - The Journal of Chemical Physics Y1 - 2018 A1 - Maksim Kouza A1 - Nguyen Truong Co A1 - Mai Suan Li A1 - Sebastian Kmiecik A1 - Andrzej Koliński A1 - Andrzej Kloczkowski A1 - Irina A. Buhimschi AB - Fibril formation resulting from protein misfolding and aggregation is a hallmark of several neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases. Despite much progress in the understanding of the protein aggregation process, the factors governing fibril formation rates and fibril stability have not been fully understood. Using lattice models, we have shown that the fibril formation time is controlled by the kinetic stability of the fibril state but not by its energy. Having performed all-atom explicit solvent molecular dynamics simulations with the GROMOS43a1 force field for full-length amyloid beta peptides Aβ40;and Aβ42;and truncated peptides, we demonstrated that kinetic stability can be accessed via mechanical stability in such a way that the higher the mechanical stability or the kinetic stability, the faster the fibril formation. This result opens up a new way for predicting fibril formation rates based on mechanical stability that may be easily estimated by steered molecular dynamics. VL - 148 UR - https://doi.org/10.1063/1.5028575 ER - TY - JOUR T1 - Modeling of Protein Structural Flexibility and Large-Scale Dynamics: Coarse-Grained Simulations and Elastic Network Models JF - International Journal of Molecular Sciences Y1 - 2018 A1 - Sebastian Kmiecik A1 - Maksim Kouza A1 - Aleksandra Dawid A1 - Andrzej Kloczkowski A1 - Andrzej Koliński AB - Fluctuations of protein three-dimensional structures and large-scale conformational transitions are crucial for the biological function of proteins and their complexes. Experimental studies of such phenomena remain very challenging and therefore molecular modeling can be a good alternative or a valuable supporting tool for the investigation of large molecular systems and long-time events. In this minireview, we present two alternative approaches to the coarse-grained (CG) modeling of dynamic properties of protein systems. We discuss two CG representations of polypeptide chains used for Monte Carlo dynamics simulations of protein local dynamics and conformational transitions, and highly simplified structure-based elastic network models of protein flexibility. In contrast to classical all-atom molecular dynamics, the modeling strategies discussed here allow the quite accurate modeling of much larger systems and longer-time dynamic phenomena. We briefly describe the main features of these models and outline some of their applications, including modeling of near-native structure fluctuations, sampling of large regions of the protein conformational space, or possible support for the structure prediction of large proteins and their complexes. VL - 19 UR - http://www.mdpi.com/1422-0067/19/11/3496 IS - 11 ER - TY - JOUR T1 - Mutation goals in the vitamin D receptor predicted by computational methods. JF - The Journal of Steroid Biochemistry and Molecular Biology Y1 - 2018 A1 - Wanda Sicinska A1 - Dominik Gront A1 - Kamil Sicinski AB - The mechanism through which nuclear receptors respond differentially to structurally distinct agonists is a poorly understood process. We present a computational method that identifies nuclear receptor amino acids that are likely involved in biological responses triggered by ligand binding. The method involves tracing how structural changes spread from the ligand binding pocket to the sites on the receptor surface, which makes it a good tool for studying allosteric effects. We employ the method to the vitamin D receptor and verify that the identified amino acids are biologically relevant using a broad range of experimental data and a genome browser. We infer that surface vitamin D receptor residues K141, R252, I260, T280, T287 and L417 are likely involved in cell differentiation and antiproliferation, whereas P122, D149, K321, E353 and Q385 are linked to carcinogenesis. VL - 183 ER - TY - JOUR T1 - Protein-peptide docking: opportunities and challenges JF - Drug Discovery Today Y1 - 2018 A1 - Maciej Pawel Ciemny A1 - Mateusz Kurcinski A1 - Karol Kamel A1 - Andrzej Koliński A1 - Nawsad Alam A1 - Ora Schueler-Furman A1 - Sebastian Kmiecik AB - Peptides have recently attracted much attention as promising drug candidates. Rational design of peptide-derived therapeutics usually requires structural characterization of the underlying protein-peptide interaction. Given that experimental characterization can be difficult, reliable computational tools are needed. In recent years, a variety of approaches have been developed for 'protein-peptide docking', that is, predicting the structure of the protein-peptide complex, starting from the protein structure and the peptide sequence, including variable degrees of information about the peptide binding site and/or conformation. In this review, we provide an overview of protein-peptide docking methods and outline their capabilities, limitations, and applications in structure-based drug design. Key challenges are also briefly discussed, such as modeling of large-scale conformational changes upon binding, scoring of predicted models, and optimal inclusion of varied types of experimental data and theoretical predictions into an integrative modeling process. VL - 23 UR - https://www.sciencedirect.com/science/article/pii/S1359644617305937 IS - 8 ER - TY - JOUR T1 - Protein–peptide docking using CABS-dock and contact information JF - Briefings in Bioinformatics Y1 - 2018 A1 - Maciej Blaszczyk A1 - Maciej Ciemny A1 - Andrzej Koliński A1 - Mateusz Kurcinski A1 - Sebastian Kmiecik AB - CABS-dock is a computational method for protein–peptide molecular docking that does not require predefinition of the binding site. The peptide is treated as fully flexible, while the protein backbone undergoes small fluctuations and, optionally, large-scale rearrangements. Here, we present a specific CABS-dock protocol that enhances the docking procedure using fragmentary information about protein–peptide contacts. The contact information is used to narrow down the search for the binding peptide pose to the proximity of the binding site. We used information on a single-chosen and randomly chosen native protein–peptide contact to validate the protocol on the peptiDB benchmark. The contact information significantly improved CABS-dock performance. The protocol has been made available as a new feature of the CABS-dock web server at http://biocomp.chem.uw.edu.pl/CABSdock UR - http://dx.doi.org/10.1093/bib/bby080 ER - TY - JOUR T1 - Role of Resultant Dipole Moment in Mechanical Dissociation of Biological Complexes JF - Molecules Y1 - 2018 A1 - Maksim Kouza A1 - Anirban Banerji A1 - Andrzej Koliński A1 - Irina Buhimschi A1 - Andrzej Kloczkowski AB - Protein-peptide interactions play essential roles in many cellular processes and their structural characterization is the major focus of current experimental and theoretical research. Two decades ago, it was proposed to employ the steered molecular dynamics (SMD) to assess the strength of protein-peptide interactions. The idea behind using SMD simulations is that the mechanical stability can be used as a promising and an efficient alternative to computationally highly demanding estimation of binding affinity. However, mechanical stability defined as a peak in force-extension profile depends on the choice of the pulling direction. Here we propose an uncommon choice of the pulling direction along resultant dipole moment (RDM) vector, which has not been explored in SMD simulations so far. Using explicit solvent all-atom MD simulations, we apply SMD technique to probe mechanical resistance of ligand-receptor system pulled along two different vectors. A novel pulling direction—when ligand unbinds along the RDM vector—results in stronger forces compared to commonly used ligand unbinding along center of masses vector. Our observation that RDM is one of the factors influencing the mechanical stability of protein-peptide complex can be used to improve the ranking of binding affinities by using mechanical stability as an effective scoring function. PB - MDPI VL - 23(8) UR - http://www.mdpi.com/1420-3049/23/8/1995 ER - TY - JOUR T1 - Synthesis, structural and antimicrobial studies of type II topoisomerase-targeted copper(II) complexes of 1,3-disubstituted thiourea ligands JF - Journal of Inorganic Biochemistry Y1 - 2018 A1 - Anna Bielenica A1 - Aleksandra Drzewiecka-Antonik A1 - Paweł Rejmak A1 - Joanna Stefańska A1 - Michał Koliński A1 - Sebastian Kmiecik A1 - Bogdan Lesyng A1 - Marta Włodarczyk A1 - Piotr Pietrzyk A1 - Marta Struga KW - Copper complexes KW - DNA gyrase KW - docking KW - FTIR KW - Thiourea AB - A series of Cu(II) complexes of 3-(trifluoromethyl)phenylthiourea derivatives was synthesized. Their structural properties were investigated by spectroscopic techniques (infrared and electron paramagnetic resonance), as well as molecular modeling. All studied coordination compounds are mononuclear complexes containing two chelating ligands bonded to the metal cation via S and deprotonated N atoms. The new chelates were evaluated for their antimicrobial potency. The complex of 1-(3,4-dichlorophenyl)-3-[3-(trifluoromethyl)phenyl]thiourea (3) presented the highest activity against Gram-positive pathogens, even stronger than the activity of its non-complexed counterpart and the reference drug. The compound also prevented the biofilm formation of methicillin-resistant and standard strains of staphylococcal cocci. The title derivatives were found to be effective inhibitors of DNA gyrase and topoisomerase IV isolated from Staphylococcus aureus. The binding modes of the ligand L3 with DNA gyrase and topoisomerase IV were presented. VL - 182 UR - http://www.sciencedirect.com/science/article/pii/S016201341730692X ER - TY - JOUR T1 - Biofunctionalisation of p-doped silicon with cytochrome c553 minimises charge recombination and enhances photovoltaic performance of the all-solid-state photosystem I-based biophotoelectrode JF - RSC Advances Y1 - 2017 A1 - Julian David Janna Olmos A1 - Philippe Becquet A1 - Dominik Gront A1 - Jarosław Sar A1 - Andrzej Dąbrowski A1 - Grzegorz Gawlik A1 - Marian Teodorczyk A1 - Dorota Pawlak A1 - Joanna Kargul AB - Surface-directed passivation of p-doped silicon (Si) substrate was achieved by its biofunctionalisation with hexahistidine (His6)-tagged cytochrome c553 (cyt c553), a soluble electroactive photosynthetic protein responsible for electron donation to photooxidised photosystem I (PSI). Five distinct variants of cyt c553 were genetically engineered by introducing the specific linker peptides of 0–19 amino acids (AA) in length between the cyt c553 holoprotein and a C-terminal His6-tag, the latter being the affinity ‘anchor’ used for the specific immobilisation of this protein on the semiconductor surface. Calculation of 2D Gibbs free energy maps for the five cyt c553 variants showed a significantly higher number of thermodynamically feasible conformations of immobilised cyt c variants containing longer linker peptides. Here we show that the distinct cyt c553-based Si bioelectrodes display some characteristics of the p–n-type diodes, albeit varying in the level of dark saturation current J0 considered as the charge recombination parameter. These combined bioinformatic and electrochemical analyses indicate that the cyt c553 variants with longer linker peptides, up to 19AA in length, allow for more structural flexibility of immobilised cyt c553 in terms of both, orientation and distance of the haem group with respect to the Si surface, and promote the efficient biopassivation of the semiconductor substrate. Incorporation of the specifically immobilised 19AA cyt c553 variant into the all-solid-state biophotoelectrodes containing light harvesting PSI module enhanced biophotovoltaic performance of the PSI biophotoelectrode compared to the analogous device devoid of cyt c553. VL - 7 UR - http://pubs.rsc.org/en/content/articlepdf/2017/ra/c7ra10895h ER - TY - JOUR T1 - Fast and Accurate Accessible Surface Area Prediction Without a Sequence Profile JF - Methods in Molecular Biology Y1 - 2017 A1 - Eshel Faraggi A1 - Maksim Kouza A1 - Yaoqi Zhou A1 - Andrzej Kloczkowski AB - A fast accessible surface area (ASA) predictor is presented. In this new approach no residue mutation profiles generated by multiple sequence alignments are used as inputs. Instead, we use only single sequence information and global features such as single-residue and two-residue compositions of the chain. The resulting predictor is both highly more efficient than sequence alignment based predictors and of comparable accuracy to them. Introduction of the global inputs significantly helps achieve this comparable accuracy. The predictor, termed ASAquick, is found to perform similarly well for so-called easy and hard cases indicating generalizability and possible usability for de-novo protein structure prediction. The source code and a Linux executables for ASAquick are available from Research and Information Systems at http://mamiris.com and from the Battelle Center for Mathematical Medicine at http://mathmed.org VL - 1484 ER - TY - CHAP T1 - The GOR Method of Protein Secondary Structure Prediction, and its Application as Protein Aggregation Prediction Tool T2 - Methods in Molecular Biology Y1 - 2017 A1 - Maksim Kouza A1 - Eshel Faraggi A1 - Andrzej Koliński A1 - Andrzej Kloczkowski AB -

The GOR method of protein secondary structure prediction is described. The original method was published by Garnier, Osguthorpe and Robson in 1978, and was one of the first successful methods to predict protein secondary structure from amino acid sequence. The method is based on the information theory, and an assumption that information function of a protein chain can be approximated by a sum of information from single residues and pairs of residues. The analysis of frequencies of occurrence of secondary structure for singlets and doublets of residues in a protein database enables prediction of secondary structure for new amino acid sequences. Because of these simple physical assumptions the GOR method has a conceptual advantage over other later developed methods such as PHD, PSIPRED and others, that are based on Machine Learning methods (like Neural Networks), give slightly better predictions, but have a “black box” nature. The GOR method has been continuously improved and modified for 30 years with the last GOR V version published in 2002, and the GOR V server developed in 2005. We discuss here the original GOR method and the GOR V program and the web server. Additionally we discuss new highly interesting and important applications of the the GOR method to chameleon sequences in protein folding simulations, and for prediction of protein aggregation propensities. Our preliminary studies show that the GOR method is a promising and efficient alternative to other protein aggregation predicting tools. This shows that the GOR method despite being almost 40 years old is still important and has significant potential in application to new scientific problems.

JF - Methods in Molecular Biology VL - 1484 SN - 978-1-4939-6404-8 ER - TY - CHAP T1 - Highly flexible protein-peptide docking using CABS-dock T2 - Methods in Molecular Biology Y1 - 2017 A1 - Maciej Ciemny A1 - Mateusz Kurcinski A1 - Konrad Kozak A1 - Andrzej Koliński A1 - Sebastian Kmiecik AB -

Protein-peptide molecular docking is a difficult modeling problem. It is even more challenging when significant conformational changes that may occur during the binding process need to be predicted. In this chapter, we demonstrate the capabilities and features of the CABS-dock server for flexible protein-peptide docking. CABS-dock allows highly efficient modeling of full peptide flexibility and significant flexibility of a protein receptor. During CABS-dock docking, the peptide folding and binding process is explicitly simulated and no information about the peptide binding site or its structure, is used. This chapter presents a successful CABS-dock use for docking a potentially therapeutic peptide to a protein target. Moreover, simulation contact maps, a new CABS-dock feature, are described and applied to the docking test case. Finally, a tutorial for running CABS-dock from the command line or command line scripts is provided. The CABS-dock web server is available from http://biocomp.chem.uw.edu.pl/CABSdock/

JF - Methods in Molecular Biology VL - 1561 ER - TY - JOUR T1 - Modeling EphB4-EphrinB2 protein–protein interaction using flexible docking of a short linear motif JF - BioMedical Engineering OnLine, 16:71 Y1 - 2017 A1 - Maciej Ciemny A1 - Mateusz Kurcinski A1 - Maciej Blaszczyk A1 - Andrzej Koliński A1 - Sebastian Kmiecik AB - Background. Many protein–protein interactions are mediated by a short linear motif. Usually, amino acid sequences of those motifs are known or can be predicted. It is much harder to experimentally characterize or predict their structure in the bound form. In this work, we test a possibility of using flexible docking of a short linear motif to predict the interaction interface of the EphB4-EphrinB2 complex (a system extensively studied for its significance in tumor progression). Methods. In the modeling, we only use knowledge about the motif sequence and experimental structures of EphB4-EphrinB2 complex partners. The proposed protocol enables efficient modeling of significant conformational changes in the short linear motif fragment during molecular docking simulation. For the docking simulations, we use the CABS-dock method for docking fully flexible peptides to flexible protein receptors (available as a server at http://biocomp.chem.uw.edu.pl/CABSdock/). Based on the docking result, the protein–protein complex is reconstructed and refined. Results. Using this novel protocol, we obtained an accurate EphB4-EphrinB2 interaction model. Conclusions The results show that the CABS-dock method may be useful as the primary docking tool in specific protein–protein docking cases similar to EphB4-EphrinB2 complex—that is, where a short linear motif fragment can be identified. UR - https://biomedical-engineering-online.biomedcentral.com/articles/10.1186/s12938-017-0362-7 ER - TY - JOUR T1 - Oligomerization of FVFLM peptides and their ability to inhibit beta amyloid peptides aggregation: consideration as a possible model JF - Physical Chemistry Chemical Physics Y1 - 2017 A1 - Maksim Kouza A1 - Anirban Banerji A1 - Andrzej Koliński A1 - Irina A. Buhimschi A1 - Andrzej Kloczkowski AB - Preeclampsia, a pregnancy-specific disorder, shares typical pathophysiological features with protein misfolding disorders including Alzheimer's disease. Characteristic for preeclampsia is the involvement of multiple proteins of which fragments of SERPINA1 and β-amyloid co-aggregate in urine and placenta of preeclamptic women. To explore the biophysical basis of this interaction, we investigated the multidimensional efficacy of the FVFLM sequence in SERPINA1, as a model inhibitory agent of β-amyloid aggregation. After studying the oligomerization of FVFLM peptides using all-atom molecular dynamics simulations with the GROMOS43a1 force field and explicit water, we report that FVFLM can aggregate and its aggregation is spontaneous with a remarkably faster rate than that recorded for KLVFF (aggregation “hot-spot” from β-amyloid). The fast kinetics of FVFLM aggregation was found to be driven primarily by core-like aromatic interactions originating from the anti-parallel orientation of complementarily uncharged strands. The conspicuously stable aggregation mechanism observed for FVFLM peptides is found not to conform to the popular 'dock-lock' scheme. We also found high propensity of FVFLM for KLVFF binding. When present, FVFLM disrupts the β-amyloid aggregation pathway and we propose that FVFLM-like peptides might be used to prevent the assembly of full-length Aβ or other pro-amyloidogenic peptides into amyloid fibrils. VL - 19 UR - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5305032/ ER - TY - CHAP T1 - One-Dimensional Structural Properties of Proteins in the Coarse-Grained CABS Model T2 - Methods in Molecular Biology Y1 - 2017 A1 - Sebastian Kmiecik A1 - Andrzej Koliński AB - Despite the significant increase in computational power, molecular modeling of protein structure using classical all-atom approaches remains inefficient, at least for most of the protein targets in the focus of biomedical research. Perhaps the most successful strategy to overcome the inefficiency problem is multiscale modeling to merge all-atom and coarse-grained models. This chapter describes a well-established CABS coarse-grained protein model. The CABS (C-Alpha, C-Beta and Side chains) model assumes a 2-4 united-atom representation of amino acids, knowledge-based force field (derived from the statistical regularities seen in known protein sequences and structures) and efficient Monte Carlo sampling schemes (MC dynamics, MC replica-exchange, and combinations). A particular emphasis is given to the unique design of the CABS force-field, which is largely defined using one-dimensional structural properties of proteins, including protein secondary structure. This chapter also presents CABS-based modeling methods, including multiscale tools for de novo structure prediction, modeling of protein dynamics and prediction of protein-peptide complexes. CABS-based tools are freely available at http://biocomp.chem.uw.edu.pl/tools JF - Methods in Molecular Biology VL - 1484 ER - TY - CHAP T1 - Predicting real-valued protein residue fluctuation using FlexPred T2 - Methods in Molecular Biology Y1 - 2017 A1 - Lenna Peterson A1 - Michal Jamroz A1 - Andrzej Koliński A1 - Daisuke Kihara AB - The conventional view of a protein structure as static provides only a limited picture.There is increasing evidence that protein dynamics are often vital to protein function including interaction with partners such as other proteins, nucleic acids, and small molecules. Considering flexibility is also important in applications such as computational protein docking and protein design. While residue flexibility is partially indicated by experimental measures such as the B‐factor from X‐ray crystallography and ensemble fluctuation from nuclear magnetic resonance (NMR) spectroscopy as well as computational molecular dynamics (MD) simulation, these techniques are resource‐intensive. In this chapter, we describe the web server and standalone version of FlexPred, which rapidly predicts absolute per‐residue fluctuation from a three‐dimensional protein structure. On a set of 592 non‐redundant structures, comparing the fluctuations predicted by FlexPred to the observed fluctuations in MD simulations showed an average correlation coefficient of 0.669 and an average root mean square error of 1.07 Å. FlexPred is available at http://kiharalab.org/flexPred/. JF - Methods in Molecular Biology VL - 1484 ER - TY - JOUR T1 - A protocol for CABS-dock protein–peptide docking driven by side-chain contact information JF - BioMedical Engineering OnLine, 16:73 Y1 - 2017 A1 - Mateusz Kurcinski A1 - Maciej Blaszczyk A1 - Maciej Ciemny A1 - Andrzej Koliński A1 - Sebastian Kmiecik AB - Background. The characterization of protein–peptide interactions is a challenge for computational molecular docking. Protein–peptide docking tools face at least two major difficulties: (1) efficient sampling of large-scale conformational changes induced by binding and (2) selection of the best models from a large set of predicted structures. In this paper, we merge an efficient sampling technique with external information about side-chain contacts to sample and select the best possible models. Methods. In this paper we test a new protocol that uses information about side-chain contacts in CABS-dock protein–peptide docking. As shown in our recent studies, CABS-dock enables efficient modeling of large-scale conformational changes without knowledge about the binding site. However, the resulting set of binding sites and poses is in many cases highly diverse and difficult to score. Results. As we demonstrate here, information about a single side-chain contact can significantly improve the prediction accuracy. Importantly, the imposed constraints for side-chain contacts are quite soft. Therefore, the developed protocol does not require precise contact information and ensures large-scale peptide flexibility in the broad contact area. Conclusions. The demonstrated protocol provides the extension of the CABS-dock method that can be practically used in the structure prediction of protein–peptide complexes guided by the knowledge of the binding interface. UR - https://biomedical-engineering-online.biomedcentral.com/articles/10.1186/s12938-017-0363-6 ER - TY - JOUR T1 - REFOLDING OF HOMOPOLYMER UNDER QUENCHED FORCE JF - Vietnam Journal of Science and Technology Y1 - 2017 A1 - Maksim Kouza A1 - Andrzej Kloczkowski A1 - Pham Dang Lan A1 - Mai Suan Li KW - distance between denaturate and transition states KW - folding pathways KW - free energy landscape KW - Go model. KW - protein refolding AB - Recently single molecule force spectroscopy has become an useful tool to study protein, DNA and RNA. However, very little attention was paid to homopolymer which plays an important role in many domains of science. In this paper we make the first attempt to decipher the free energy landscape of homopolymer using the external force as reaction coordinate. The impact of the quenched force on the free energy landscape was studied using simplified coarse-grain Go model. Similar to protein, we have obtained a clear switch from the thermal regime to force-driven regime. The distance between the denatured state and transition state in the temperature-driven regime is smaller than in the force-driven one.  Having a rugged free energy landscape without a pronounced funnel the homopolymer folding is much slower than that of protein making study of homopolymer very time consuming. VL - 55 (6A) UR - http://vjs.ac.vn/index.php/jst/article/view/12360 ER - TY - JOUR T1 - SURPASS Low-Resolution Coarse-Grained Protein Modeling JF - Journal of Chemical Theory and Computation Y1 - 2017 A1 - Aleksandra Dawid A1 - Dominik Gront A1 - Andrzej Koliński KW - coarse-grained models KW - de novo protein folding KW - empirical force field KW - knowledge-based potential KW - protein modeling KW - reduced models AB - Coarse-grained modeling of biomolecules has a very important role in molecular biology. In this work we present a novel SURPASS (Single United Residue per Pre-Averaged Secondary Structure fragment) model of proteins that can be an interesting alternative for existing coarse-grained models. The design of the model is unique and strongly supported by the statistical analysis of structural regularities characteristic for protein systems. Coarse-graining of protein chain structures assumes a single center of interactions per residue and accounts for preaveraged effects of four adjacent residue fragments. Knowledge-based statistical potentials encode complex patterns of these fragments. Using the Replica Exchange Monte Carlo sampling scheme and a generic version of the SURPASS force field we performed test simulations of a representative set of single-domain globular proteins. The method samples a significant part of conformational space and reproduces protein structures, including native-like, with surprisingly good accuracy. Future extension of the SURPASS model on large biomacromolecular systems is briefly discussed. VL - 13(11) UR - https://pubs.acs.org/doi/10.1021/acs.jctc.7b00642 ER - TY - JOUR T1 - Switch from thermal to force-driven pathways of protein refolding JF - The Journal of Chemical Physics Y1 - 2017 A1 - Maksim Kouza A1 - Pham Dang Lan A1 - Alexander M. Gabovich A1 - Andrzej Koliński A1 - Mai Suan Li AB -

The impact of the quenched force on protein folding pathways and free energy landscape was studied in detail. Using the coarse-grain Go model, we have obtained the low, middle, and high force regimes for protein refolding under the quenched force. The folding pathways in the low force regime coincide with the thermal ones. A clear switch from thermal folding pathways to force-driven pathways in the middle force regime was observed. The distance between the denatured state and transition state xf in the temperature-driven regime is smaller than in the force-driven one. The distance xf obtained in the middle force regime is consistent with the available experimental data suggesting that atomic force microscopy experiments deal with the force-regime which is just above the thermal one.

VL - 146 UR - http://aip.scitation.org/doi/10.1063/1.4979201 ER - TY - JOUR T1 - Toward more efficient simulations of slow processes in large biomolecular systems: Comment on "Ligand diffusion in proteins via enhanced sampling in molecular dynamics" by Jakub Rydzewski and Wieslaw Nowak. JF - Physics of Life Reviews Y1 - 2017 A1 - Andrzej Koliński AB - Molecular Dynamics is a powerful computational method for studying the structure, energetics and dynamics of molecular objects. Since the available computing power grows rapidly, satisfying over the last 50 years the famous Moore's Law, larger and more complex systems can be effectively modeled using the MD tools. Nevertheless, many problems of molecular biology or biophysics are still beyond the reach of efficient applicability with classical MD. Simply, interesting biomolecular systems are often huge, composed of thousands (many thousands) of atoms, and the characteristic time scale of important processes can range from seconds to several days. Modeling of ligand diffusion, discussed in the review by Rydzewski and Nowak, is one of such complex MD tasks located on the border of the applicability of classical MD algorithms. The problems discussed in the review are important not only for molecular physics and chemistry, but they could also be very interesting for rational drug design, especially since experimental ligand diffusion data are difficult to collect and interpret. VL - 22–23 UR - https://www.sciencedirect.com/science/article/pii/S1571064517301008?via%3Dihub ER - TY - JOUR T1 - 5-HT2 receptor affinity, docking studies and pharmacological evaluation of a series of 1,3-disubstituted thiourea derivatives JF - European Journal of Medicinal Chemistry Y1 - 2016 A1 - Anna Bielenica A1 - Ewa Kedzierska A1 - Michal Kolinski A1 - Sebastian Kmiecik A1 - Andrzej Koliński A1 - Ferdinando Fiorino A1 - Beatrice Severino A1 - Elisa Magli A1 - Ilaria Rossi A1 - Paola Massarelli A1 - Anna E Kozioł A1 - Aleksandra Sawczenko A1 - Marta Struga AB - A series of 10 thiourea derivatives have been synthesized by the reaction of aromatic amine with a substituted aryl (compounds 1-3, 6-8) and alkylphenyl (4, 5, 9, 10) isothiocyanates. Their in vitro and in vivo pharmacological properties were studied. Among the evaluated compounds, two displayed very high affinity for the 5-HT2A receptor (1 – 0.043 nM and 5 – 0.6 nM), being selective over the 5-HT2C receptor. Derivatives 3, 5, 9, 10 by 70- 89 % diminished L-5-HTP-induced head twitch episodes. Compounds 1 and 5 as the 5-HT2A receptor antagonists produced a dose-dependent decrease in the number of DOI-elicited HTR. Compounds 1-5 strongly reduced amphetamine-evoked hyperactivity in rodents. In another test, 1 and 2 caused hyperthermia in mice, whereas 9 and 10 led to hypothermia. Antinociceptive and anticonvulsant properties of selected derivatives were demonstrated. Molecular docking studies using a homology model of 5-HT2A revealed a significant role of hydrogen bonds between both thiourea NH groups and Asp155/Tyr370 residues, as well as Pi-Pi interaction with Phe339. VL - 116 IS - 30 ER - TY - JOUR T1 - Coarse-Grained Protein Models and Their Applications JF - Chemical Reviews Y1 - 2016 A1 - Sebastian Kmiecik A1 - Dominik Gront A1 - Michal Kolinski A1 - Lukasz Wieteska A1 - Aleksandra Dawid A1 - Andrzej Koliński AB - The traditional computational modeling of protein structure, dynamics and interactions remains difficult for many protein systems. It is mostly due to the size of protein conformational spaces and required simulation timescales that are still too large to be studied in atomistic detail. Lowering the level of protein representation from all-atom to coarse-grained opens up new possibilities for studying protein systems. In this review we provide an overview of coarse-grained models focusing on their design, including choices of representation, models of energy functions, sampling of conformational space, and applications in the modeling of protein structure, dynamics and interactions. A more detailed description is given for applications of coarse-grained models suitable for efficient combinations with all-atom simulations in multiscale modeling strategies. VL - 116 UR - https://pubs.acs.org/doi/10.1021/acs.chemrev.6b00163 IS - 14 ER - TY - JOUR T1 - Coarse-grained simulations of membrane insertion and folding of small helical proteins using CABS model JF - Journal of Chemical Information and Modeling Y1 - 2016 A1 - Wojciech Pulawski A1 - Michal Jamroz A1 - Michal Kolinski A1 - Andrzej Koliński A1 - Sebastian Kmiecik AB - The CABS coarse-grained model is a well-established tool for modeling globular proteins (predicting their structure, dynamics and interactions). Here we introduce an extension of CABS representation and force field (CABS-membrane) to the modeling of the effect of biological membrane environment on the structure of membrane proteins. We validate the CABS-membrane model in folding simulations of 10 short helical membrane proteins not using any knowledge about their structure. The simulations start from random protein conformations placed outside the membrane environment and allow for full flexibility of the modeled proteins during their spontaneous insertion into the membrane. In the resulting trajectories, we have found models close to the experimental membrane structures. We also attempted to select the correctly folded models using simple filtering followed by structural clustering combined with reconstruction to all-atom representation and all-atom scoring. In conclusion, the CABS-membrane model is a promising approach for further development towards modeling of large protein-membrane systems. VL - 56 UR - https://pubs.acs.org/doi/abs/10.1021/acs.jcim.6b00350 IS - 11 ER - TY - JOUR T1 - Ensemble-based evaluation for protein structure models JF - Bioinformatics Y1 - 2016 A1 - Michal Jamroz A1 - Andrzej Koliński A1 - Daisuke Kihara AB - Motivation: Comparing protein tertiary structures is a fundamental procedure in structural biology and protein bioinformatics. Structure comparison is important particularly for evaluating computa- tional protein structure models. Most of the model structure evaluation methods perform rigid body superimposition of a structure model to its crystal structure and measure the difference of the corresponding residue or atom positions between them. However, these methods neglect in- trinsic flexibility of proteins by treating the native structure as a rigid molecule. Because different parts of proteins have different levels of flexibility, for example, exposed loop regions are usually more flexible than the core region of a protein structure, disagreement of a model to the native needs to be evaluated differently depending on the flexibility of residues in a protein. Results: We propose a score named FlexScore for comparing protein structures that consider flexibility of each residue in the native state of proteins. Flexibility information may be extracted from experiments such as NMR or molecular dynamics simulation. FlexScore considers an ensemble of conformations of a protein described as a multivariate Gaussian distribution of atomic displace- ments and compares a query computational model with the ensemble. We compare FlexScore with other commonly used structure similarity scores over various examples. FlexScore agrees with experts’ intuitive assessment of computational models and provides information of practical usefulness of models. VL - 32 UR - http://bioinformatics.oxfordjournals.org/lookup/doi/10.1093/bioinformatics/btw262 ER - TY - Generic T1 - Flexible protein-peptide docking using CABS-dock with knowledge about the binding site T2 - Proceedings of the International Work-conference on Bioinformatics and BIOmedical engineering (IWWBIO) in Granada, Spain, 195-201, arXiv:1605.09269 Y1 - 2016 A1 - Mateusz Kurcinski A1 - Maciej Ciemny A1 - Maciej Blaszczyk A1 - Andrzej Koliński A1 - Sebastian Kmiecik AB - Despite considerable efforts, structural prediction of protein-peptide complexes is still a very challenging task, mainly due to two reasons: high flexibility of the peptides and transient character of their interactions with proteins. Recently we have developed an automated web server CABS-dock (http://biocomp.chem.uw.edu.pl/CABSdock), which conducts flexible protein-peptide docking without any knowledge about the binding site. Our method allows for full flexibility of the peptide, whereas the flexibility of the receptor is restricted to near native conformations considering the main chain, and full flexibility of the side chains. Performance of the CABS-dock server was thoroughly tested on a benchmark of 171 test cases, both bound and unbound. Evaluation of the obtained results showed overall good performance of the method, especially that no information of the binding site was used. From unsuccessful experiments we learned that the accuracy of docking might be significantly improved, if only little information of the binding site was considered. In fact, in real-life applications user typically has access to some data indicating the location and/or structure of the binding site. In the current work, we test and demonstrate the performance of the CABS-dock server with two new features. The first one allows to utilize the knowledge about receptor residue(s) constituting the binding site, and the second one allows to enforce the desired secondary structure on the peptide structure. Based on the given example, we observe significant improvement of the docking accuracy in comparison to the default CABS-dock mode. JF - Proceedings of the International Work-conference on Bioinformatics and BIOmedical engineering (IWWBIO) in Granada, Spain, 195-201, arXiv:1605.09269 ER - TY - JOUR T1 - Modeling of protein-peptide interactions using the CABS-dock web server for binding site search and flexible docking JF - Methods Y1 - 2016 A1 - Maciej Blaszczyk A1 - Mateusz Kurcinski A1 - Maksim Kouza A1 - Lukasz Wieteska A1 - Aleksander Debinski A1 - Andrzej Koliński A1 - Sebastian Kmiecik KW - CABS-dock KW - flexible docking KW - molecular docking KW - peptide binding KW - peptide folding KW - protein-peptide docking AB - Protein-peptide interactions play essential functional roles in living organisms and their structural characterization is a hot subject of current experimental and theoretical research. Computational modeling of the structure of protein-peptide interactions is usually divided into two stages: prediction of the binding site at a protein receptor surface, and then docking (and modeling) the peptide structure into the known binding site. This paper presents a comprehensive CABS-dock method for the simultaneous search of binding sites and flexible protein-peptide docking, available as a user’s friendly web server. We present example CABS-dock results obtained in the default CABS-dock mode and using its advanced options that enable the user to increase the range of flexibility for chosen receptor fragments or to exclude user-selected binding modes from docking search. Furthermore, we demonstrate a strategy to improve CABS-dock performance by assessing the quality of models with classical molecular dynamics. Finally, we discuss the promising extensions and applications of the CABS-dock method and provide a tutorial appendix for the convenient analysis and visualization of CABS-dock results. The CABS-dock web server is freely available at http://biocomp.chem.uw.edu.pl/CABSdock/ VL - 93 ER - TY - JOUR T1 - Protein secondary structure prediction using a small training set (compact model) combined with a Complex-valued neural network approach JF - BMC Bioinformatics Y1 - 2016 A1 - Shamima Rashid A1 - Saras Saraswathi A1 - Andrzej Kloczkowski A1 - Suresh Sundaram A1 - Andrzej Koliński AB - Background Protein secondary structure prediction (SSP) has been an area of intense research interest. Despite advances in recent methods conducted on large datasets, the estimated upper limit accuracy is yet to be reached. Since the predictions of SSP methods are applied as input to higher-level structure prediction pipelines, even small errors may have large perturbations in final models. Previous works relied on cross validation as an estimate of classifier accuracy. However, training on large numbers of protein chains compromises the classifier ability to generalize to new sequences. This prompts a novel approach to training and an investigation into the possible structural factors that lead to poor predictions. Here, a small group of 55 proteins termed the compact model is selected from the CB513 dataset using a heuristics-based approach. In a prior work, all sequences were represented as probability matrices of residues adopting each of Helix, Sheet and Coil states, based on energy calculations using the C-Alpha, C-Beta, Side-chain (CABS) algorithm. The functional relationship between the conformational energies computed with CABS force-field and residue states is approximated using a classifier termed the Fully Complex-valued Relaxation Network (FCRN). The FCRN is trained with the compact model proteins. Results The performance of the compact model is compared with traditional cross-validated accuracies and blind-tested on a dataset of G Switch proteins, obtaining accuracies of ∼81 %. The model demonstrates better results when compared to several techniques in the literature. A comparative case study of the worst performing chain identifies hydrogen bond contacts that lead to Coil ⇔ Sheet misclassifications. Overall, mispredicted Coil residues have a higher propensity to participate in backbone hydrogen bonding than correctly predicted Coils. Conclusions The implications of these findings are: (i) the choice of training proteins is important in preserving the generalization of a classifier to predict new sequences accurately and (ii) SSP techniques sensitive in distinguishing between backbone hydrogen bonding and side-chain or water-mediated hydrogen bonding might be needed in the reduction of Coil ⇔ Sheet misclassifications. VL - 17 IS - 362 ER - TY - JOUR T1 - Protein-peptide molecular docking with large-scale conformational changes: the p53-MDM2 interaction JF - Scientific Reports Y1 - 2016 A1 - Maciej Ciemny A1 - Aleksander Debinski A1 - Marta Paczkowska A1 - Andrzej Koliński A1 - Mateusz Kurcinski A1 - Sebastian Kmiecik AB - Protein-peptide interactions are often associated with large-scale conformational changes that are difficult to study either by classical molecular modeling or by experiment. Recently, we have developed the CABS-dock method for flexible protein-peptide docking that enables large-scale rearrangements of the protein chain. In this study, we use CABS-dock to investigate the binding of the p53-MDM2 complex, an element of the cell cycle regulation system crucial for anti-cancer drug design. Experimental data suggest that p53-MDM2 binding is affected by significant rearrangements of a lid region - the N-terminal highly flexible MDM2 fragment; however, the details are not clear. The large size of the highly flexible MDM2 fragments makes p53-MDM2 intractable for exhaustive binding dynamics studies using atomistic models. We performed extensive dynamics simulations using the CABS-dock method, including large-scale structural rearrangements of MDM2 flexible regions. Without a priori knowledge of the p53 peptide structure or its binding site, we obtained near-native models of the p53-MDM2 complex. The simulation results match well the experimental data and provide new insights into the possible role of the lid fragment in p53 binding. The presented case study demonstrates that CABS-dock methodology opens up new opportunities for protein-peptide docking with large-scale changes of the protein receptor structure. VL - 6 ER - TY - Generic T1 - Towards protein-protein docking with significant structural changes using CABS-dock T2 - Proceedings of the International Work-conference on Bioinformatics and BIOmedical engineering (IWWBIO) in Granada, Spain, 207-213, arXiv:1605.09266 Y1 - 2016 A1 - Maciej Ciemny A1 - Mateusz Kurcinski A1 - Andrzej Koliński A1 - Sebastian Kmiecik AB - The protein-protein interactions (PPIs) are crucial for understanding the majority of cellular processes. PPIs play important role in gene transcription regulation, cellular signaling, molecular basis of immune response and more. Moreover, a disruption of hese mechanisms is frequently postulated as a possible cause of diseases such as Alzheimer's or cancer. For many of biologically relevant cases the structure of protein-protein complexes remain unknown. Therefore computational techniques, including molecular docking, have become a valuable part of drug discovery pipelines. Unfortunately, none of the widely used protein-protein docking tools is free from serious limitations. Typically, in docking simulations the protein flexibility is either completely neglected or very limited. Additionally, some knowledge of the approximate location and/or the shape of the active site is also required. Such limitations arise mostly from the enormous number of degrees of freedom of protein-protein systems. In this paper, an efficient computational method for protein-protein docking is proposed and initially tested on a single docking case. The proposed method is based on a two-step procedure. In the first step, CABS-dock web server for protein-peptide docking is used to dock a peptide, which is the appropriate protein fragment responsible for the protein-protein interaction, to the other protein partner. During peptide docking, no knowledge about the binding site, nor the peptide structure, is used and the peptide is allowed to be fully flexible. In the second step, the docked peptide is used in the structural adjustment of protein complex partners. The proposed method allowed us to obtain a high accuracy model, therefore it provides a promising framework for further advances. JF - Proceedings of the International Work-conference on Bioinformatics and BIOmedical engineering (IWWBIO) in Granada, Spain, 207-213, arXiv:1605.09266 ER - TY - JOUR T1 - AGGRESCAN3D (A3D): server for prediction of aggregation properties of protein structures JF - Nucleic Acids Research Y1 - 2015 A1 - Rafael Zambrano A1 - Michal Jamroz A1 - Agata Szczasiuk A1 - Jordi Pujols A1 - Sebastian Kmiecik A1 - Salvador Ventura AB - Protein aggregation underlies an increasing number of disorders and constitutes a major bottleneck in the development of therapeutic proteins. Our present understanding on the molecular determinants of protein aggregation has crystalized in a series of predictive algorithms to identify aggregation-prone sites. A majority of these methods rely only on sequence. Therefore, they find difficulties to predict the aggregation properties of folded globular proteins, where aggregation-prone sites are often not contiguous in sequence or buried inside the native structure. The AGGRESCAN3D (A3D) server overcomes these limitations by taking into account the protein structure and the experimental aggregation propensity scale from the well-established AGGRESCAN method. Using the A3D server, the identified aggregation-prone residues can be virtually mutated to design variants with increased solubility, or to test the impact of pathogenic mutations. Additionally, A3D server enables to take into account the dynamic fluctuations of protein structure in solution, which may influence aggregation propensity. This is possible in A3D Dynamic Mode that exploits the CABS-flex approach for the fast simulations  of flexibility of globular proteins. The A3D server can be accessed at http://biocomp.chem.uw.edu.pl/A3D/ VL - 43 (W1) ER - TY - JOUR T1 - CABS-dock web server for the flexible docking of peptides to proteins without prior knowledge of the binding site JF - Nucleic Acids Research Y1 - 2015 A1 - Mateusz Kurcinski A1 - Michal Jamroz A1 - Maciej Blaszczyk A1 - Andrzej Koliński A1 - Sebastian Kmiecik KW - CABS-dock KW - flexible docking KW - molecular docking KW - peptide binding KW - peptide folding KW - protein-peptide docking KW - protein-peptide interactions AB - Protein-peptide interactions play a key role in cell functions. Their structural characterization, though challenging, is important for the discovery of new drugs. The CABS-dock web server provides an interface for modeling protein-peptide interactions using a highly efficient protocol for the flexible docking of peptides to proteins. While other docking algorithms require pre-defined localization of the binding site, CABS-dock doesn’t require such knowledge. Given a protein receptor structure and a peptide sequence (and starting from random conformations and positions of the peptide), CABS-dock performs simulation search for the binding site allowing for full flexibility of the peptide and small fluctuations of the receptor backbone. This protocol was extensively tested over the largest dataset of non-redundant protein-peptide interactions available to date (including bound and unbound docking cases). For over 80% of bound and unbound dataset cases, we obtained models with high or medium accuracy (sufficient for practical applications). Additionally, as optional features, CABS-dock can exclude user-selected binding modes from docking search or to increase the level of flexibility for chosen receptor fragments. CABS-dock is freely available as a web server at http://biocomp.chem.uw.edu.pl/CABSdock VL - 43 (W1) ER - TY - JOUR T1 - Coarse-Grained Modeling of Peptide Docking Associated With Large Conformation Transitions of The Binding Protein: Troponin I Fragment–Troponin C System JF - Molecules Y1 - 2015 A1 - Jacek Wabik A1 - Mateusz Kurcinski A1 - Andrzej Koliński AB - Most of the current docking procedures are focused on fine conformational adjustments of assembled complexes and fail to reproduce large-scale protein motion. In this paper, we test a new modeling approach developed to address this problem. CABS-dock is a versatile and efficient tool for modeling the structure, dynamics and interactions of protein complexes. The docking protocol employs a coarse-grained representation of proteins, a simplified model of interactions and advanced protocols for conformational sampling. CABS-dock is one of the very few tools that allow unrestrained docking with large conformational freedom of the receptor. In an example application we modeled the process of complex assembly between two proteins: Troponin C (TnC) and the N-terminal helix of Troponin I (TnI N-helix), which occurs in vivo during muscle contraction. Docking simulations illustrated how the TnC molecule undergoes significant conformational transition on complex formation, a phenomenon that can be modeled only when protein flexibility is properly accounted for. This way our procedure opens up a new possibility for studying mechanisms of protein complex assembly, which may be a supporting tool for rational drug design. VL - 20 IS - 6 ER - TY - JOUR T1 - Improving thermal stability of thermophilic l-threonine aldolase from Thermotoga maritima. JF - Journal of Biotechnology Y1 - 2015 A1 - Lukasz Wieteska A1 - Maksim Ionov A1 - Janusz Szemraj A1 - Claudia Feller A1 - Andrzej Koliński A1 - Dominik Gront AB - Threonine aldolase (TA) catalyzes a reversible reaction, in which threonine is decomposed into glycine and acetaldehyde. The same enzyme can be used to catalyze aldol reaction between glycine and a variety of aromatic and aliphatic aldehydes, thus creating various alpha-amino-alcohols. Therefore, TA is a very promising enzyme that could be used to prepare biologically active compounds or building blocks for pharmaceutical industry. Rational design was applied to thermophilic TA from Thermotoga maritima to improve thermal stability by the incorporation of salt and disulfide bridges between subunits in the functional tetramer. An activity assay together with CD analysis and Western-blot detection was used to evaluate mutants. Except one, each of the designed mutants preserved activity toward the natural substrate. One of the 10 proposed single point mutants, P56C, displayed significantly enhanced stability compared to the wild type (WT). Its initial activity was not affected and persisted longer than WT, proportionally to increased stability. Additionally one of the mutants, W86E, displayed enhanced activity, with stability similar to WT. Higher activity may be explained by a subtle change in active site availability. Salt bridge formation between glutamic acid at position 86 and arginine at position 120 in the neighboring chain may be responsible for the slight shift of the chain fragment, thus creating wider access to the active site both for the substrate and PLP. VL - 199 ER - TY - JOUR T1 - KnotProt: a database of proteins with knots and slipknots JF - Nucleic Acids Research Y1 - 2015 A1 - Michal Jamroz A1 - Wanda Niemyska A1 - Eric J Rawdon A1 - Andrzej Stasiak A1 - Kenneth C Millett A1 - Piotr Sułkowski A1 - Joanna I. Sulkowska AB - The protein topology database KnotProt, http://knotprot.cent.uw.edu.pl/ , collects information about protein structures with open polypeptide chains forming knots or slipknots. The knotting complexity of the catalogued proteins is presented in the form of a matrix diagram that shows users the knot type of the entire polypeptide chain and of each of its subchains. The pattern visible in the matrix gives the knotting fingerprint of a given protein and permits users to determine, for example, the minimal length of the knotted regions (knots’ core size) or the depth of a knot, i.e. how many aminoacids can be removed from either end of the catalogued protein structure before converting it from a knot to a different type of knot. In addition, the database presents extensive information about the biological function of proteins with non-trivial knotting and the families and fold types of these proteins. As an additional feature, the KnotProt database enables users to submit protein or polymer structures and generate their knotting fingerprints. http://knotprot.cent.uw.edu.pl/ VL - 43 UR - http://nar.oxfordjournals.org/content/43/D1/D306 IS - D1 ER - TY - JOUR T1 - Prediction of the optimal set of contacts to fold the smallest knotted protein. JF - J Phys Condens Matter Y1 - 2015 A1 - Dabrowski-Tumanski, P A1 - Jarmolinska, A I A1 - Joanna I. Sulkowska AB - Knotted protein chains represent a new motif in protein folds. They have been linked to various diseases, and recent extensive analysis of the Protein Data Bank shows that they constitute 1.5% of all deposited protein structures. Despite thorough theoretical and experimental investigations, the role of knots in proteins still remains elusive. Nonetheless, it is believed that knots play an important role in mechanical and thermal stability of proteins. Here, we perform a comprehensive analysis of native, shadow-specific and non-native interactions which describe free energy landscape of the smallest knotted protein (PDB id 2efv). We show that the addition of shadow-specific contacts in the loop region greatly enhances folding kinetics, while the addition of shadow-specific contacts along the C-terminal region (H3 or H4) results in a new folding route with slower kinetics. By means of direct coupling analysis (DCA) we predict non-native contacts which also can accelerate kinetics. Next, we show that the length of the C-terminal knot tail is responsible for the shape of the free energy barrier, while the influence of the elongation of the N-terminus is not significant. Finally, we develop a concept of a minimal contact map sufficient for 2efv protein to fold and analyze properties of this protein using this map. VL - 27 IS - 35 ER - TY - JOUR T1 - Preformed template fluctuations promote fibril formation: Insights from lattice and all-atom models JF - The Journal of Chemical Physics Y1 - 2015 A1 - Maksim Kouza A1 - Nguyen Truong Co A1 - Phuong Hoang Nguyen A1 - Andrzej Koliński A1 - Mai Suan Li AB - Fibril formation resulting from protein misfoding and aggregation is a hallmark of several neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases. Despite the fact that the fibril formation process is very slow and thus poses a significant challenge for theoretical and experimental studies, a number of alternative pictures of molecular mechanisms of amyloid fibril formation have been recently proposed. What seems to be common for the majority of the proposed models is that fibril elongation involves the formation of pre-nucleus seeds prior to the creation of a critical nucleus. Once the size of the pre-nucleus seed reaches the critical nucleus, its thermal fluctuations are expected to be small and the resulting nucleus provides a template for sequential (one-by-one) accomodation of added monomers. The effect of template fluctuations on fibril formation rates has not been explored either experimentally or theoretically so far. In this paper we make the first attempt at solving this problem by two sets of simulations. To mimic small template fluctuations, in one set, monomers of the preformed template are kept fixed, while in the other set they are allowed to fluctuate. The kinetics of addition of a new peptide onto the template is explored using all-atom simulations with explicit water and the GROMOS96 43a1 force field and simple lattice models. Our result demonstrates that preformed template fluctuations can modulate protein aggregation rates and pathways. The association of a nascent monomer with the template obeys the kinetics partitioning mechanism where the intermediate state occurs in a fraction of routes to the protofibril. It was shown that template immobility greatly increases the time of incorporating a new peptide into the preformed template compared to the fluctuating template case. This observation has also been confirmed by simulation using lattice models and may be invoked to understand the role of template fluctuations in slowing down fibril elongation in vivo. VL - 142 ER - TY - JOUR T1 - BioShell-Threading: versatile Monte Carlo package for protein 3D threading. JF - BMC Bioinformatics Y1 - 2014 A1 - Pawel Gniewek A1 - Andrzej Koliński A1 - Andrzej Kloczkowski A1 - Dominik Gront AB - BACKGROUND: The comparative modeling approach to protein structure prediction inherently relies on a template structure. Before building a model such a template protein has to be found and aligned with the query sequence. Any error made on this stage may dramatically affects the quality of result. There is a need, therefore, to develop accurate and sensitive alignment protocols. RESULTS: BioShell threading software is a versatile tool for aligning protein structures, protein sequences or sequence profiles and query sequences to a template structures. The software is also capable of suboptimal alignment generation. It can be executed as an application from the UNIX command line, or as a set of Java classes called from a script or a Java application. The implemented Monte Carlo search engine greatly facilitates the development and benchmarking of new alignment scoring schemes evenwhen the functions exhibit non-deterministic polynomial-time complexity. CONCLUSIONS: Numerical experiments indicate that the new threading application offers template detection abilities and provides much better alignments than other methods. The package along with documentation and examples is available at: http://bioshell.pl/threading3d. VL - 15 IS - 1 ER - TY - JOUR T1 - CABS-flex predictions of protein flexibility compared with NMR ensembles JF - Bioinformatics Y1 - 2014 A1 - Michal Jamroz A1 - Andrzej Koliński A1 - Sebastian Kmiecik AB - Motivation: Identification of flexible regions of protein structures is important for understanding of their biological functions. Recently, we have developed a fast approach for predicting protein structure fluctuations from a single protein model: the CABS-flex. CABS-flex was shown to be an efficient alternative to conventional all-atom molecular dynamics (MD). In this work, we evaluate CABS-flex and MD predictions by comparison with protein structural variations within NMR ensembles. Results: Based on a benchmark set of 140 proteins, we show that the relative fluctuations of protein residues obtained from CABS-flex are well correlated to those of NMR ensembles. On average, this correlation is stronger than that between MD and NMR ensembles. In conclusion, CABS-flex is useful and complementary to MD in predicting of protein regions that undergo conformational changes and the extent of such changes. Availability: The CABS-flex is freely available to all users at http://biocomp.chem.uw.edu.pl/CABSflex. VL - 30 IS - 15 ER - TY - CHAP T1 - Coarse-Grained Modeling of Protein Dynamics T2 - Computational Methods to Study the Structure and Dynamics of Biomolecules and Biomolecular Processes, Springer Series in Bio-/Neuroinformatics, Adam Liwo, Ed. Y1 - 2014 A1 - Sebastian Kmiecik A1 - Jacek Wabik A1 - Michal Kolinski A1 - Maksim Kouza A1 - Andrzej Koliński KW - coarse-grained modeling KW - protein dynamics AB - Simulations of protein dynamics may work on different levels of molecular detail. The levels of simplification (coarse-graining) can range from very low to atomic resolution and may concern different simulation aspects (including protein representation, interaction schemes or models of molecular motion). So-called coarse-grained (CG) models offer many advantages, unreachable by classical simulation tools, as demonstrated in numerous studies of protein dynamics. Followed by a brief introduction, we present example applications of CG models for efficient predictions of biophysical mechanisms. We discuss the following topics: mechanisms of chaperonin action, mechanical properties of proteins, membrane proteins, protein-protein interactions and intrinsically unfolded proteins. Presently, these areas represent emerging application fields of CG simulation models. JF - Computational Methods to Study the Structure and Dynamics of Biomolecules and Biomolecular Processes, Springer Series in Bio-/Neuroinformatics, Adam Liwo, Ed. PB - Springer Berlin Heidelberg VL - 1 ER - TY - Generic T1 - Coarse-grained modeling of protein structure, dynamics and protein-protein interactions T2 - TASK Quarterly Y1 - 2014 A1 - Andrzej Koliński A1 - Sebastian Kmiecik A1 - Michal Jamroz A1 - Maciej Blaszczyk A1 - Maksim Kouza A1 - Mateusz Kurcinski AB - Theoretical prediction of protein structures and dynamics is essential for understanding the molecular basis of drug action, metabolic and signaling pathways in living cells, designing new technologies in the life science and material sciences. We developed and validated a novel multiscale methodology for the study of protein folding processes including flexible docking of proteins and peptides. The new modeling technique starts from coarse-grained large-scale simulations, followed by selection of the most plausible final structures and intermediates and, finally, by an all-atom rectification of the obtained structures. Except for the most basic bioinformatics tools, the entire computational methodology is based on the models and algorithms developed in our lab. The coarse-grained simulations are based on a high-resolution lattice representation of protein structures, a knowledge based statistical force field and efficient Monte Carlo dynamics schemes, including Replica Exchange algorithms. This paper focuses on the description of the coarse-grained CABS model and its selected applications. JF - TASK Quarterly VL - 18 ER - TY - CHAP T1 - Coarse-Grained Protein Models in Structure Prediction T2 - Computational Methods to Study the Structure and Dynamics of Biomolecules and Biomolecular Processes, Springer Series in Bio-/Neuroinformatics, Adam Liwo, Ed. Y1 - 2014 A1 - Maciej Blaszczyk A1 - Dominik Gront A1 - Sebastian Kmiecik A1 - Katarzyna Ziolkowska A1 - Marta Panek A1 - Andrzej Koliński AB - The knowledge of the three-dimensional structure of proteins is crucial for understanding many important biological processes. Most biologically important proteins are too large to handle for the classical simulation tools. In such cases, coarse-grained (CG) models nowadays offer various opportunities for efficient conformational sampling and thus prediction of the three-dimensional structure. A variety of CG models have been proposed, each based on a similar framework consisting of a set of conceptual components such as protein representation, force field, sampling, etc. In this chapter we discuss these components, highlighting ideas which have proven to be the most successful. As CG methods are usually part of multistage procedures, we also describe approaches used for the incorporation of homology data and all-atom reconstruction methods. JF - Computational Methods to Study the Structure and Dynamics of Biomolecules and Biomolecular Processes, Springer Series in Bio-/Neuroinformatics, Adam Liwo, Ed. VL - 1 ER - TY - JOUR T1 - Connecting thermal and mechanical protein (un)folding landscapes JF - Biophysical Journal Y1 - 2014 A1 - Li Sun A1 - Jeffrey K. Noel A1 - Joanna I. Sulkowska A1 - Herbert Levine A1 - José N. Onuchic AB - Molecular dynamics simulations supplement single-molecule pulling experiments by providing the possibility of examining the full free energy landscape using many coordinates. Here, we use an all-atom structure-based model to study the force and temperature dependence of the unfolding of the protein filamin by applying force at both termini. The unfolding time-force relation τ(F) indicates that the force-induced unfolding behavior of filamin can be characterized into three regimes: barrier-limited low- and intermediate-force regimes, and a barrierless high-force regime. Slope changes of τ(F) separate the three regimes. We show that the behavior of τ(F) can be understood from a two-dimensional free energy landscape projected onto the extension X and the fraction of native contacts Q. In the low-force regime, the unfolding rate is roughly force-independent due to the small (even negative) separation in X between the native ensemble and transition state ensemble (TSE). In the intermediate-force regime, force sufficiently separates the TSE from the native ensemble such that τ(F) roughly follows an exponential relation. This regime is typically explored by pulling experiments. While X may fail to resolve the TSE due to overlap with the unfolded ensemble just below the folding temperature, the overlap is minimal at lower temperatures where experiments are likely to be conducted. The TSE becomes increasingly structured with force, whereas the average order of structural events during unfolding remains roughly unchanged. The high-force regime is characterized by barrierless unfolding, and the unfolding time approaches a limit of ∼10 μs for the highest forces we studied. Finally, a combination of X and Q is shown to be a good reaction coordinate for almost the entire force range. VL - 107(12) ER - TY - Generic T1 - Flexible docking of the fragment of the troponin I to the troponin C T2 - IWBBIO 2014 (2nd International Work-Conference on Bioinformatics and Biomedical Engineering) Y1 - 2014 A1 - Jacek Wabik A1 - Mateusz Kurcinski A1 - Andrzej Koliński AB - Most of the current docking procedures are focused on fine conformational adjustment of assembled complexes and fail to reproduce large-scale motions. Our approach based on the coarse-grained modeling of flexible macromolecules overcomes these limitations. CABSDock procedure used in this work employs coarse-grained model CABS – efficient and versatile tool for modeling of proteins structure, dynamics and interactions [1-4]. In this work CABSDock was used to model assembly process of troponin C(TnC) with the N-terminal helix of the troponin I(TnI). TnC/TnI binding was investigated for both cardiac and skeletal troponin. TnI fragment was modeled allowing its unbiased movement. Entire structure of TnC domain was also treated as fully flexible, although its motion was restricted to near-native conformations. Binding of the TnI fragment changed the orientation between both domains. This picture provides valuable insight into mechanistic description of troponin function. JF - IWBBIO 2014 (2nd International Work-Conference on Bioinformatics and Biomedical Engineering) CY - Granada, Spain ER - TY - JOUR T1 - Key Factors Governing Fibril Formation Of Proteins: Insights From Simulations And Experiments JF - Task Quarterly Y1 - 2014 A1 - Nguyen Truong Co A1 - Man Hoang Viet A1 - Phan Minh Truong A1 - Maksim Kouza A1 - Mai Suan Li AB - Fibril formation of proteins and peptides is associated with a large group of major human diseases, including Alzheimer’s disease, prion disorders, amyotrophic lateral sclerosis, type 2 diabetes, etc. Therefore, understanding the key factors that govern this process is of paramount importance. The fibrillogenesis of polypeptide chains depends on their intrinsic properties as well as on the external conditions. In this mini-review we discuss the relationship between fibril formation kinetics and the sequence, aromaticity, hydrophobicity, charge and population of the so called fibril-prone conformation in a monomer state. The higher the population, the faster is the fibril elongation and this dependence may be described by a single exponential function. This observation opens up a new way to understand the fibrillogenesis of bio-molecules at the monomer level. We will also discuss the influence of the environment with focus on the recently observed dual effect of crowders on the aggregation rates of polypeptide chains. VL - 18 IS - 3 ER - TY - Generic T1 - Mechanical unfolding of DDFLN4 studied by the coarse-grained knowledge-based CABS model T2 - TASK Quarterly Y1 - 2014 A1 - Maksim Kouza A1 - Michal Jamroz A1 - Dominik Gront A1 - Sebastian Kmiecik A1 - Andrzej Koliński AB - Mechanical unfolding of the fourth domain of Distyostelium discoideum filamin (DDFLN4) was studied using a CABS – coarse-grained knowledge-based protein model. Our study demonstrates that CABS is capable of reproducing the unfolding free energy landscape of protein unfolding and highlights an important role of non-native interactions in the protein unfolding process. The obtained three peaks in the force-extension profile suggest a four-state picture of DDFLN4 protein unfolding and correspond reasonably to the results of the all-atom simulation in explicit solvent. JF - TASK Quarterly VL - 18 ER - TY - JOUR T1 - Mechanism of Folding and Binding of an Intrinsically Disordered Protein as Revealed by Ab Initio Simulations JF - Journal of Chemical Theory and Computation Y1 - 2014 A1 - Mateusz Kurcinski A1 - Andrzej Koliński A1 - Sebastian Kmiecik KW - CABS-dock KW - coarse-grained modeling KW - flexible docking KW - intrinsically disordered proteins KW - molecular docking KW - peptide binding KW - peptide folding KW - protein dynamics KW - protein-peptide docking AB - A complex of the phosphorylated kinase-inducible domain (pKID) with its interacting domain (KIX) is a model system for studies of mechanisms by which intrinsically unfolded proteins perform their functions. These mechanisms are not fully understood. Using an efficient coarse-grained model, ab initio simulations were performed of the coupled folding and binding of the pKID to the KIX. The simulations start from an unbound, randomly positioned and disordered pKID structure. During the simulations the pKID chain and its position remain completely unrestricted, while the KIX backbone is limited to near-native fluctuations. Ab initio simulations of such large-scale conformational transitions, unaffected by any knowledge about the bound pKID structure, remain inaccessible to classical simulations. Our simulations recover an ensemble of transient encounter complexes in good agreement with experimental results. We find that a key folding and binding step is linked to the formation of weak native interactions between a preformed native-like fragment of a pKID helix and KIX surface. Once that nucleus forms, the pKID chain may condense from largely disordered encounter ensemble to a natively bound and ordered conformation. The observed mechanism is reminiscent of a nucleation-condensation model, a common scenario for folding of globular proteins. VL - 10 IS - 6 ER - TY - JOUR T1 - Pierced Lasso Bundles are a New Class of Knot Motifs JF - PLoS computational biology Y1 - 2014 A1 - Haglund, Ellinor A1 - Joanna I. Sulkowska A1 - Noel, Jeffrey K. A1 - Lammert, H A1 - Onuchic, José N. A1 - Jennings, Patricia A AB - A four-helix bundle is a well-characterized motif often used as a target for designed pharmaceutical therapeutics and nutritional supplements. Recently, we discovered a new structural complexity within this motif created by a disulphide bridge in the long-chain helical bundle cytokine leptin. When oxidized, leptin contains a disulphide bridge creating a covalent-loop through which part of the polypeptide chain is threaded (as seen in knotted proteins). We explored whether other proteins contain a similar intriguing knot-like structure as in leptin and discovered 11 structurally homologous proteins in the PDB. We call this new helical family class the Pierced Lasso Bundle (PLB) and the knot-like threaded structural motif a Pierced Lasso (PL). In the current study, we use structure-based simulation to investigate the threading/folding mechanisms for all the PLBs along with three unthreaded homologs as the covalent loop (or lasso) in leptin is important in folding dynamics and activity. We find that the presence of a small covalent loop leads to a mechanism where structural elements slipknot to thread through the covalent loop. Larger loops use a piercing mechanism where the free terminal plugs through the covalent loop. Remarkably, the position of the loop as well as its size influences the native state dynamics, which can impact receptor binding and biological activity. This previously unrecognized complexity of knot-like proteins within the helical bundle family comprises a completely new class within the knot family, and the hidden complexity we unraveled in the PLBs is expected to be found in other protein structures outside the four-helix bundles. The insights gained here provide critical new elements for future investigation of this emerging class of proteins, where function and the energetic landscape can be controlled by hidden topology, and should be take into account in ab initio predictions of newly identified protein targets. VL - 10(6) ER - TY - CHAP T1 - Protocols for efficient simulations of long time protein dynamics using coarse-grained CABS model T2 - Protein structure prediction (3rd Edition), Methods in Molecular Biology, Daisuke Kihara, Ed. Y1 - 2014 A1 - Michal Jamroz A1 - Andrzej Koliński A1 - Sebastian Kmiecik KW - coarse-grained modeling KW - protein dynamics AB - Coarse-grained (CG) modeling is a well-acknowledged simulation approach for getting insight into long timescale protein folding events at reasonable computational cost. Depending on the design of a CG model, the simulation protocols vary from highly case-specific – requiring user-defined assumptions about the folding scenario, to more sophisticated blind prediction methods for which only a protein sequence is required. Here we describe the framework protocol for the simulations of long-term dynamics of globular proteins, with the use of the CABS CG protein model and sequence data. The simulations can start from a random or selected (e.g. native) structure. The described protocol has been validated using experimental data for protein folding model systems – the prediction results agreed well with the experimental results. JF - Protein structure prediction (3rd Edition), Methods in Molecular Biology, Daisuke Kihara, Ed. VL - 1137 ER - TY - JOUR T1 - Structure prediction of the second extracellular loop in G-protein-coupled receptors JF - Biophysical Journal Y1 - 2014 A1 - Sebastian Kmiecik A1 - Michal Jamroz A1 - Michal Kolinski AB - G protein-coupled receptors (GPCRs) play key roles in living organisms. Therefore it is important to determine their functional structures. The second extracellular loop (ECL2) is a functionally important region of GPCRs which poses significant challenge for computational structure prediction methods. In this work, we evaluated CABS, a well-established protein modeling tool for predicting ECL2 structure in thirteen GPCRs. The ECL2s (with between 13 and 34 residues) are predicted in an environment of other extracellular loops being fully flexible and the transmembrane domain fixed in its X-ray conformation. The modeling procedure utilized theoretical predictions of ECL2 secondary structure and experimental constraints on disulfide bridges. Our approach yielded ensembles of low-energy conformers and the most populated conformers that contained models close to the available X-ray structures. Predicted loop fragments resemble X-ray structures with comparable accuracy to those obtained by other state-of-the-art methods. Our results extend other studies by including newly crystallized GPCRs. VL - 106 IS - 11 ER - TY - JOUR T1 - CABS-flex: server for fast simulation of protein structure fluctuations JF - Nucleic Acids Research Y1 - 2013 A1 - Michal Jamroz A1 - Andrzej Koliński A1 - Sebastian Kmiecik KW - molecular dynamics KW - near-native dynamics KW - protein dynamics KW - protein flexibility KW - simulation AB - The CABS-flex server (http://biocomp.chem.uw.edu.pl/CABSflex) implements CABS-model-based protocol for the fast simulations of near-native dynamics of globular proteins. In this application, the CABS model was shown to be a computationally efficient alternative to all-atom molecular dynamics-a classical simulation approach. The simulation method has been validated on a large set of molecular dynamics simulation data. Using a single input (user-provided file in PDB format), the CABS-flex server outputs an ensemble of protein models (in all-atom PDB format) reflecting the flexibility of the input structure, together with the accompanying analysis (residue mean-square-fluctuation profile and others). The ensemble of predicted models can be used in structure-based studies of protein functions and interactions. VL - 41 UR - http://nar.oxfordjournals.org/cgi/content/full/gkt332 IS - W1 ER - TY - JOUR T1 - CABS-fold: server for the de novo and consensus-based prediction of protein structure JF - Nucleic Acids Research Y1 - 2013 A1 - Maciej Blaszczyk A1 - Michal Jamroz A1 - Sebastian Kmiecik A1 - Andrzej Koliński KW - coarse-grained modeling KW - homology modeling KW - protein structure prediction AB - The CABS-fold web server provides tools for protein structure prediction from sequence only (de novo modeling) and also using alternative templates (consensus modeling). The web server is based on the CABS modeling procedures ranked in previous CASP competitions (Critical Assessment of techniques for protein Structure Prediction) as one of the leading approaches for de novo< and template-based modeling. Except for template data, fragmentary distance restraints can also be incorporated into the modeling process. The web server output is a coarse-grained trajectory of generated conformations, its Jmol representation and predicted models in all-atom resolution (together with accompanying analysis). CABS-fold can be freely accessed at http://biocomp.chem.uw.edu.pl/CABSfold VL - 41 IS - W1 ER - TY - JOUR T1 - ClusCo: clustering and comparison of protein models JF - BMC Bioinformatics Y1 - 2013 A1 - Michal Jamroz A1 - Andrzej Koliński AB - BACKGROUND: The development, optimization and validation of protein modeling methods require efficient tools forstructural comparison. Frequently, a large number of models need to be compared with the targetnative structure. The main reason for the development of Clusco software was to create a high-throughput tool for all-versus-all comparison, because calculating similarity matrix is the one of thebottlenecks in the protein modeling pipeline. RESULTS: Clusco is fast and easy-to-use software for high-throughput comparison of protein models with dif-ferent similarity measures (cRMSD, dRMSD, GDT_TS, TM-Score, MaxSub, Contact Map Overlap)and clustering of the comparison results with standard methods: K-means Clustering or HierarchicalAgglomerative Clustering. CONCLUSIONS: The application was highly optimized and written in C/C++, including the code for parallel execu-tion on CPU and GPU, which resulted in a significant speedup over similar clustering and scoringcomputation programs. VL - 14 IS - 1 ER - TY - JOUR T1 - Combining Coarse-Grained Protein Models with Replica-Exchange All-Atom Molecular Dynamics JF - International Journal of Molecular Sciences Y1 - 2013 A1 - Jacek Wabik A1 - Sebastian Kmiecik A1 - Dominik Gront A1 - Maksim Kouza A1 - Andrzej Koliński KW - coarse-grained modeling KW - molecular dynamics KW - multiscale modeling KW - protein dynamics AB - We describe a combination of all-atom simulations with CABS, a well-established coarse-grained protein modeling tool, into a single multiscale protocol. The simulation method has been tested on the C-terminal beta hairpin of protein G, a model system of protein folding. After reconstructing atomistic details, conformations derived from the CABS simulation were subjected to replica-exchange molecular dynamics simulations with OPLS-AA and AMBER99sb force fields in explicit solvent. Such a combination accelerates system convergence several times in comparison with all-atom simulations starting from the extended chain conformation, demonstrated by the analysis of melting curves, the number of native-like conformations as a function of time and secondary structure propagation. The results strongly suggest that the proposed multiscale method could be an efficient and accurate tool for high-resolution studies of protein folding dynamics in larger systems. VL - 14 UR - http://www.mdpi.com/1422-0067/14/5/9893 ER - TY - JOUR T1 - Consistent View of Protein Fluctuations from All-Atom Molecular Dynamics and Coarse-Grained Dynamics with Knowledge-Based Force-Field JF - Journal of Chemical Theory and Computation Y1 - 2013 A1 - Michal Jamroz A1 - Modesto Orozco A1 - Andrzej Koliński A1 - Sebastian Kmiecik KW - molecular dynamics KW - near-native dynamics KW - protein dynamics KW - protein flexibility KW - simulation AB - It is widely recognized that atomistic Molecular Dynamics (MD), a classical simulation method, captures the essential physics of protein dynamics. That idea is supported by a theoretical study showing that various MD force-fields provide a consensus picture of protein fluctuations in aqueous solution [Rueda, M. et al. Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 796-801]. However, atomistic MD cannot be applied to most biologically relevant processes due to its limitation to relatively short time scales. Much longer time scales can be accessed by properly designed coarse-grained models. We demonstrate that the aforementioned consensus view of protein dynamics from short (nanosecond) time scale MD simulations is fairly consistent with the dynamics of the coarse-grained protein model - the CABS model. The CABS model employs stochastic dynamics (a Monte Carlo method) and a knowledge-based force-field, which is not biased toward the native structure of a simulated protein. Since CABS-based dynamics allows for the simulation of entire folding (or multiple folding events) in a single run, integration of the CABS approach with all-atom MD promises a convenient (and computationally feasible) means for the long-time multiscale molecular modeling of protein systems with atomistic resolution. VL - 9 SN - 1549-9618 UR - http://dx.doi.org/10.1021/ct300854w IS - 1 JO - J. Chem. Theory Comput. ER - TY - JOUR T1 - Distributions of amino acids suggest that certain residue types more effectively determine protein secondary structure JF - Journal of Molecular Modeling Y1 - 2013 A1 - Saras Saraswathi A1 - J. L. Fernández-Martínez A1 - Andrzej Koliński A1 - Robert L. Jernigan A1 - Andrzej Kloczkowski AB - Exponential growth in the number of available protein sequences is unmatched by the slower growth in the number of structures. As a result, the development of efficient and fast protein secondary structure prediction methods is essential for the broad comprehension of protein structures. Computational methods that can efficiently determine secondary structure can in turn facilitate protein tertiary structure prediction, since most methods rely initially on secondary structure predictions. Recently, we have developed a fast learning optimized prediction methodology (FLOPRED) for predicting protein secondary structure (Saraswathi et al. in JMM 18:4275, 2012). Data are generated by using knowledge-based potentials combined with structure information from the CATH database. A neural network-based extreme learning machine (ELM) and advanced particle swarm optimization (PSO) are used with this data to obtain better and faster convergence to more accurate secondary structure predicted results. A five-fold cross-validated testing accuracy of 83.8 % and a segment overlap (SOV) score of 78.3 % are obtained in this study. Secondary structure predictions and their accuracy are usually presented for three secondary structure elements: α-helix, β-strand and coil but rarely have the results been analyzed with respect to their constituent amino acids. In this paper, we use the results obtained with FLOPRED to provide detailed behaviors for different amino acid types in the secondary structure prediction. We investigate the influence of the composition, physico-chemical properties and position specific occurrence preferences of amino acids within secondary structure elements. In addition, we identify the correlation between these properties and prediction accuracy. The present detailed results suggest several important ways that secondary structure predictions can be improved in the future that might lead to improved protein design and engineering. VL - 19 IS - 10 ER - TY - JOUR T1 - Hysteresis as a Marker for Complex, Overlapping Landscapes in Proteins. JF - Journal of Physicak Chemistry Letters Y1 - 2013 A1 - Andrews, Benjamin T A1 - Capraro, Dominique T A1 - Joanna I. Sulkowska A1 - Onuchic, José N A1 - Jennings, Patricia A AB - Topologically complex proteins fold by multiple routes as a result of hard-to-fold regions of the proteins. Oftentimes these regions are introduced into the protein scaffold for function and increase frustration in the otherwise smooth-funneled landscape. Interestingly, while functional regions add complexity to folding landscapes, they may also contribute to a unique behavior referred to as hysteresis. While hysteresis is predicted to be rare, it is observed in various proteins, including proteins containing a unique peptide cyclization to form a fluorescent chromophore as well as proteins containing a knotted topology in their native fold. Here, hysteresis is demonstrated to be a consequence of the decoupling of unfolding events from the isomerization or hula-twist of a chromophore in one protein and the untying of the knot in a second protein system. The question now is- can hysteresis be a marker for the interplay of landscapes where complex folding and functional regions overlap? VL - 4 IS - 1 ER - TY - JOUR T1 - Identifying knots in proteins. JF - Biochemical Society Transactions Y1 - 2013 A1 - Millett, Kenneth C A1 - Rawdon, Eric J A1 - Stasiak, Andrzej A1 - Joanna I. Sulkowska KW - Animals KW - Humans KW - Models, Molecular KW - Protein Conformation KW - Proteins AB - Polypeptide chains form open knots in many proteins. How these knotted proteins fold and finding the evolutionary advantage provided by these knots are among some of the key questions currently being studied in the protein folding field. The detection and identification of protein knots are substantial challenges. Different methods and many variations of them have been employed, but they can give different results for the same protein. In the present article, we review the various knot identification algorithms and compare their relative strengths when applied to the study of knots in proteins. We show that the statistical approach based on the uniform closure method is advantageous in comparison with other methods used to characterize protein knots. VL - 41 IS - 2 ER - TY - JOUR T1 - Knot localization in proteins. JF - Biochemical Society Transactions Y1 - 2013 A1 - Rawdon, Eric J A1 - Millett, Kenneth C A1 - Joanna I. Sulkowska A1 - Stasiak, Andrzej KW - Animals KW - Humans KW - Models, Molecular KW - Protein Conformation KW - Proteins AB - The backbones of proteins form linear chains. In the case of some proteins, these chains can be characterized as forming linear open knots. The knot type of the full chain reveals only limited information about the entanglement of the chain since, for example, subchains of an unknotted protein can form knots and subchains of a knotted protein can form different types of knots than the entire protein. To understand fully the entanglement within the backbone of a given protein, a complete analysis of the knotting within all of the subchains of that protein is necessary. In the present article, we review efforts to characterize the full knotting complexity within individual proteins and present a matrix that conveys information about various aspects of protein knotting. For a given protein, this matrix identifies the precise localization of knotted regions and shows the knot types formed by all subchains. The pattern in the matrix can be considered as a knotting fingerprint of that protein. We observe that knotting fingerprints of distantly related knotted proteins are strongly conserved during evolution and discuss how some characteristic motifs in the knotting fingerprints are related to the structure of the knotted regions and their possible biological role. VL - 41 IS - 2 ER - TY - JOUR T1 - Knotting a Protein in Explicit Solvent JF - The Journal of Physical Chemistry Letters Y1 - 2013 A1 - Jeffrey K. Noel A1 - José N. Onuchic A1 - Joanna I. Sulkowska AB - Recently, experiments have confirmed that trefoil knotted proteins can fold spontaneously, consistent with predictions from simulations of simplified protein models. These simulations suggest folding the knot involves threading the protein terminal across a twisted loop via a slipknot configuration. Here, we report unbiased all-atom explicit-solvent simulations of the knotting dynamics of a protein. In simulations totaling 40 μs, we find that 5 out of 15 simulations reach the knotted native state when initiated from unknotted, slipknotted intermediates. The completed threading events had durations of 0.1–2 μs. Comparison of explicit-solvent to structure-based simulations shows that similar native contacts are responsible for threading the slipknot through the loop; however, competition between native and non-native salt bridges during threading results in increased energetic roughness. Overall, these simulations support a slipknotting mechanism for proteins with complex topology, and help verify that simplified models are useful tools for studying knotted proteins. VL - 4 UR - http://pubs.acs.org/doi/abs/10.1021/jz401842f ER - TY - JOUR T1 - Knotting pathways in proteins. JF - Biochemical Society Transactions Y1 - 2013 A1 - Joanna I. Sulkowska A1 - Noel, Jeffrey K A1 - Ramírez-Sarmiento, César A A1 - Rawdon, Eric J A1 - Millett, Kenneth C A1 - Onuchic, José N KW - Animals KW - Humans KW - Protein Conformation KW - Protein Engineering KW - Protein Folding KW - Proteins KW - Thermodynamics AB - Most proteins, in order to perform their biological function, have to fold to a compact native state. The increasing number of knotted and slipknotted proteins identified suggests that proteins are able to manoeuvre around topological barriers during folding. In the present article, we review the current progress in elucidating the knotting process in proteins. Although we concentrate on theoretical approaches, where a knotted topology can be unambiguously detected, comparison with experiments is also reviewed. Numerical simulations suggest that the folding process for small knotted proteins is composed of twisted loop formation and then threading by either slipknot geometries or flipping. As the size of the knotted proteins increases, particularly for more deeply threaded termini, the prevalence of traps in the free energy landscape also increases. Thus, in the case of longer knotted and slipknotted proteins, the folding mechanism is probably supported by chaperones. Overall, results imply that knotted proteins can be folded efficiently and survive evolutionary pressure in order to perform their biological functions. VL - 41 IS - 2 ER - TY - JOUR T1 - A structure-based model fails to probe the mechanical unfolding pathways of the titin I27 domain JF - The Journal of Chemical Physics Y1 - 2013 A1 - Maksim Kouza A1 - Chin-Kun Hu A1 - Mai Suan Li A1 - Andrzej Koliński KW - biochemistry KW - biomechanics KW - free energy KW - mechanical stability KW - molecular biophysics KW - molecular configurations AB - We discuss the use of a structure based Cα-Go model and Langevin dynamics to study in detail the mechanical properties and unfolding pathway of the titin I27 domain. We show that a simple Go-model does detect correctly the origin of the mechanical stability of this domain. The unfolding free energy landscape parameters xu and ΔG‡, extracted from dependencies of unfolding forces on pulling speeds, are found to agree reasonably well with experiments. We predict that above v = 104 nm/s the additional force-induced intermediate state is populated at an end-to-end extension of about 75 Å. The force-induced switch in the unfolding pathway occurs at the critical pulling speed vcrit ≈ 106–107 nm/s. We argue that this critical pulling speed is an upper limit of the interval where Bell's theory works. However, our results suggest that the Go-model fails to reproduce the experimentally observed mechanical unfolding pathway properly, yielding an incomplete picture of the free energy landscape. Surprisingly, the experimentally observed intermediate state with the A strand detached is not populated in Go-model simulations over a wide range of pulling speeds. The discrepancy between simulation and experiment is clearly seen from the early stage of the unfolding process which shows the limitation of the Go model in reproducing unfolding pathways and deciphering the complete picture of the free energy landscape. PB - AIP VL - 139 UR - http://link.aip.org/link/?JCP/139/065103/1 ER - TY - JOUR T1 - Assessment of the free binding energy of 1,25-dihydroxyvitamin D3 and its analogs with the human VDR receptor model JF - Acta Biochimica Polonica Y1 - 2012 A1 - Karol Kamel A1 - Andrzej Koliński AB - 1,25-dihydroxyvitamin D(3) has quite significant anticancer properties, but its strong calcemic effect in principle excludes it as a potential anticancer drug. Currently, a lot of effort is being devoted to develop potent anticancer analogs of 1,25-dihydroxyvitamin D(3) that would not induce hypercalcemia during therapy. In this work, the free binding energy of the VDR receptor with 1,25-dihydroxyvitamin D(3) and its three potent analogs (EB 1089, KH 1060 and RO 25-9022) is calculated and compared with each other. With this approach, we could estimate the relative binding affinity of the most potent analog, RO 25-9022, and also revealed a quite distinct mechanism of its interaction with VDR. VL - 59 IS - 4 ER - TY - JOUR T1 - BioShell Threader: protein homology detection based on sequence profiles and secondary structure profiles JF - Nucleic Acids Research Y1 - 2012 A1 - Dominik Gront A1 - Maciej Blaszczyk A1 - Piotr Wojciechowski A1 - Andrzej Koliński AB - The BioShell package has recently been extended with a web server for protein homology detection based on profile-to-profile alignment (known as 1D threading). Its aim is to assign structural templates to each domain of the query. The server uses sequence profiles that describe observed sequence variability and secondary structure profiles providing expected probability for a certain secondary structure type at a given position in a protein. Three independent predictors are used to increase the rate of successful predictions. Careful evaluation shows that there is nearly 80% chance that the query sequence belongs to the same SCOP family as the top scoring template. The Bioshell Threader server is freely available at: http://www.bioshell.pl/threader/. VL - 40 UR - http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3394251&tool=pmcentrez&rendertype=abstract ER - TY - JOUR T1 - Chameleonicity and folding of the C-fragment of TOP7 JF - EPL (Europhysics Letters) Y1 - 2012 A1 - M. L. Gaye A1 - C. Hardwick A1 - Maksim Kouza A1 - Ulrich H. E. Hansmann AB - Using a specifically designed Go-model we have performed all-atom simulations of the C-fragment of TOP7. Our results support previous results (see Mohanty S. et al. , Proc. Natl. Acad. Sci. U.S.A. , 105 (2008) 8004; Mohanty S. and Hansmann U. H. E., J. Phys. Chem. B , 112 (2008) 15134) that indicate folding of this protein through configurations with non-native secondary structure. The N-terminal residues form first an extension of a subsequent α-helix, before finally refolding into a β-strand that completes a three-stranded β-sheet in the final structure. We show that mutations which reduce the "chameleonicity" of N-terminal residues (by increasing the propensity for "strandness" and reducing that for "helicity") lead to folding into the same structure but with reduced folding rates and larger free-energy barriers. VL - 97 UR - http://stacks.iop.org/0295-5075/97/i=6/a=68003 ER - TY - JOUR T1 - Coarse-grained modeling of mucus barrier properties JF - Biophysical Journal Y1 - 2012 A1 - Pawel Gniewek A1 - Andrzej Koliński KW - Adhesives KW - Adhesives: chemistry KW - Adhesives: metabolism KW - Glycocalyx KW - Glycocalyx: chemistry KW - Glycocalyx: metabolism KW - Models KW - Molecular KW - Mucins KW - Mucins: chemistry KW - Mucins: metabolism KW - Mucus KW - Mucus: chemistry KW - Mucus: cytology KW - Mucus: metabolism KW - Nanoparticles KW - Nanoparticles: chemistry KW - Protein Conformation KW - Surface Properties AB -

We designed a simple coarse-grained model of the glycocalyx layer, or adhesive mucus layer (AML), covered by mucus gel (luminal mucus layer) using a polymer lattice model and stochastic sampling (replica exchange Monte Carlo) for canonical ensemble simulations. We assumed that mucin MUC16 is responsible for the structural properties of the AML. Other mucins that are much smaller in size and less relevant for layer structure formation were not included. We further assumed that the system was in quasi-equilibrium. For systems with surface coverage and concentrations of model mucins mimicking physiological conditions, we determined the equilibrium distribution of inert nanoparticles within the mucus layers using an efficient replica exchange Monte Carlo sampling procedure. The results show that the two mucus layers penetrate each other only marginally, and the bilayer imposes a strong barrier for nanoparticles, with the AML layer playing a crucial role in the mucus barrier.

VL - 102 UR - http://www.ncbi.nlm.nih.gov/pubmed/22339855 ER - TY - Generic T1 - Coarse-grained Protein Modeling: Dynamics, Folding Pathways and Mechanical Unfolding T2 - From Computational Biophysics to Systems Biology (CBSB11) Proceedings Y1 - 2012 A1 - Andrzej Koliński A1 - Maciej Blaszczyk A1 - Sebastian Kmiecik AB - Coarse-grained protein modeling tool, CABS, is used in multiscale modeling of protein dynamics. It is demonstrated that the stochastic (Monte Carlo) dynamics, combined with all-atom refinement of the coarse-grained structures follows observed in experiments folding pathways of small proteins. The model is also used in model studies of chaperonin-assisted protein folding. It is shown that Iterative Annealing Mechanism of chaperonin action, where periodic distortion of the polypeptide chains by non-specific hydrophobic interactions can promote rapid folding and leads to a decrease in folding temperature. It is also demonstrated how chaperonin action prevents kinetically trapped conformations and modulates the observed folding mechanisms from nucleation-condensation to a more framework-like. Finally, the CABS model is used in simulations of mechanical unfolding, providing new ways for interpretation of Atomic Force Microscopy experiments. JF - From Computational Biophysics to Systems Biology (CBSB11) Proceedings VL - 8 ER - TY - JOUR T1 - Conservation of complex knotting and slipknotting patterns in proteins. JF - Proceedings of the National Academy of Sciences of the United States of America Y1 - 2012 A1 - Joanna I. Sulkowska A1 - Rawdon, Eric J A1 - Millett, Kenneth C A1 - Onuchic, José N A1 - Stasiak, Andrzej KW - Protein Conformation KW - Protein Folding KW - Proteins AB - While analyzing all available protein structures for the presence of knots and slipknots, we detected a strict conservation of complex knotting patterns within and between several protein families despite their large sequence divergence. Because protein folding pathways leading to knotted native protein structures are slower and less efficient than those leading to unknotted proteins with similar size and sequence, the strict conservation of the knotting patterns indicates an important physiological role of knots and slipknots in these proteins. Although little is known about the functional role of knots, recent studies have demonstrated a protein-stabilizing ability of knots and slipknots. Some of the conserved knotting patterns occur in proteins forming transmembrane channels where the slipknot loop seems to strap together the transmembrane helices forming the channel. VL - 109 IS - 26 ER - TY - JOUR T1 - Elastic network normal modes provide a basis for protein structure refinement JF - The Journal of Chemical Physics Y1 - 2012 A1 - Pawel Gniewek A1 - Andrzej Koliński A1 - Robert L. Jernigan A1 - Andrzej Kloczkowski AB -

It is well recognized that thermal motions of atoms in the protein native state, the fluctuations about the minimum of the global free energy, are well reproduced by the simple elastic network models (ENMs) such as the anisotropic network model (ANM). Elastic network models represent protein dynamics as vibrations of a network of nodes (usually represented by positions of the heavy atoms or by the C($\alpha$) atoms only for coarse-grained representations) in which the spatially close nodes are connected by harmonic springs. These models provide a reliable representation of the fluctuational dynamics of proteins and RNA, and explain various conformational changes in protein structures including those important for ligand binding. In the present paper, we study the problem of protein structure refinement by analyzing thermal motions of proteins in non-native states. We represent the conformational space close to the native state by a set of decoys generated by the I-TASSER protein structure prediction server utilizing template-free modeling. The protein substates are selected by hierarchical structure clustering. The main finding is that thermal motions for some substates, overlap significantly with the deformations necessary to reach the native state. Additionally, more mobile residues yield higher overlaps with the required deformations than do the less mobile ones. These findings suggest that structural refinement of poorly resolved protein models can be significantly enhanced by reduction of the conformational space to the motions imposed by the dominant normal modes.

VL - 136 UR - http://www.ncbi.nlm.nih.gov/pubmed/22612113 ER - TY - JOUR T1 - Energy landscape of knotted protein folding. JF - Proceedings of the National Academy of Sciences of the United States of America Y1 - 2012 A1 - Joanna I. Sulkowska A1 - Noel, Jeffrey K A1 - Onuchic, José N KW - Evolution, Molecular KW - Kinetics KW - Models, Molecular KW - Molecular Dynamics Simulation KW - Mutation KW - Protein Folding KW - Proteins AB - Recent experiments have conclusively shown that proteins are able to fold from an unknotted, denatured polypeptide to the knotted, native state without the aid of chaperones. These experiments are consistent with a growing body of theoretical work showing that a funneled, minimally frustrated energy landscape is sufficient to fold small proteins with complex topologies. Here, we present a theoretical investigation of the folding of a knotted protein, 2ouf, engineered in the laboratory by a domain fusion that mimics an evolutionary pathway for knotted proteins. Unlike a previously studied knotted protein of similar length, we see reversible folding/knotting and a surprising lack of deep topological traps with a coarse-grained structure-based model. Our main interest is to investigate how evolution might further select the geometry and stiffness of the threading region of the newly fused protein. We compare the folding of the wild-type protein to several mutants. Similarly to the wild-type protein, all mutants show robust and reversible folding, and knotting coincides with the transition state ensemble. As observed experimentally, our simulations show that the knotted protein folds about ten times slower than an unknotted construct with an identical contact map. Simulated folding kinetics reflect the experimentally observed rollover in the folding limbs of chevron plots. Successful folding of the knotted protein is restricted to a narrow range of temperature as compared to the unknotted protein and fits of the kinetic folding data below folding temperature suggest slow, nondiffusive dynamics for the knotted protein. VL - 109 IS - 44 ER - TY - JOUR T1 - Fast learning optimized prediction methodology (FLOPRED) for protein secondary structure prediction JF - Journal of Molecular Modeling Y1 - 2012 A1 - Saras Saraswathi A1 - Juan Luis Fernandez Martinez A1 - Andrzej Koliński A1 - Robert L. Jernigan A1 - Andrzej Kloczkowski KW - knowledge-based potentials KW - learning KW - machine KW - neural networks KW - particle swarm optimization KW - protein secondary structure prediction AB -

Computational methods are rapidly gaining importance in the field of structural biology, mostly due to the explosive progress in genome sequencing projects and the large disparity between the number of sequences and the number of structures. There has been an exponential growth in the number of available protein sequences and a slower growth in the number of structures. There is therefore an urgent need to develop computational methods to predict structures and identify their functions from the sequence. Developing methods that will satisfy these needs both efficiently and accurately is of paramount importance for advances in many biomedical fields, including drug development and discovery of biomarkers. A novel method called fast learning optimized prediction methodology (FLOPRED) is proposed for predicting protein secondary structure, using knowledge-based potentials combined with structure information from the CATH database. A neural network-based extreme learning machine (ELM) and advanced particle swarm optimization (PSO) are used with this data that yield better and faster convergence to produce more accurate results. Protein secondary structures are predicted reliably, more efficiently and more accurately using FLOPRED. These techniques yield superior classification of secondary structure elements, with a training accuracy ranging between 83 % and 87 % over a widerange of hidden neurons and a cross-validated testing accuracy ranging between 81 % and 84 % and a segment overlap (SOV) score of 78 % that are obtained with different sets of proteins. These results are comparable to other recently published studies, but are obtained with greater efficiencies, in terms of time and cost.

VL - 18 UR - http://www.ncbi.nlm.nih.gov/pubmed/22562230 ER - TY - JOUR T1 - Folding Simulations of the A and B Domains of Protein G JF - The Journal of Physical Chemistry B Y1 - 2012 A1 - Maksim Kouza A1 - Ulrich H. E. Hansmann AB - We study wild type and mutants of the A and B domain of protein G using all-atom Go-models. Our data substantiate the usefulness of such simulation for probing the folding mechanism of proteins and demonstrate that multifunnel versions of such models also allow probing of more complicated funnel landscapes. In our case, such models reproduce the experimentally observed distributions of the GA98 and GB98 mutants which differ only by one residue but fold into different structures. They also reveal details on the folding mechanism in these two proteins. VL - 116 UR - http://pubs.acs.org/doi/abs/10.1021/jp210497h ER - TY - JOUR T1 - From coarse-grained to atomic-level characterization of protein dynamics: transition state for the folding of B domain of protein A JF - The Journal of Physical Chemistry B Y1 - 2012 A1 - Sebastian Kmiecik A1 - Dominik Gront A1 - Maksim Kouza A1 - Andrzej Koliński KW - coarse-grained modeling KW - molecular dynamics KW - multiscale modeling KW - protein dynamics AB - Atomic-level molecular dynamics simulations are widely used for the characterization of the structural dynamics of proteins; however, they are limited to shorter time scales than the duration of most of the relevant biological processes. Properly designed coarse-grained models that trade atomic resolution for efficient sampling allow access to much longer time-scales. In-depth understanding of the structural dynamics, however, must involve atomic details. In this study, we tested a method for the rapid reconstruction of all-atom models from $\alpha$ carbon atom positions in the application to convert a coarse-grained folding trajectory of a well described model system: the B domain of protein A. The results show that the method and the spatial resolution of the resulting coarse-grained models enable computationally inexpensive reconstruction of realistic all-atom models. Additionally, by means of structural clustering, we determined the most persistent ensembles of the key folding step, the transition state. Importantly, the analysis of the overall structural topologies suggests a dominant folding pathway. This, together with the all-atom characterization of the obtained ensembles, in the form of contact maps, matches the experimental results well. VL - 116 UR - http://www.ncbi.nlm.nih.gov/pubmed/22486297 ER - TY - JOUR T1 - Genomics-aided structure prediction. JF - Proceedings of the National Academy of Sciences of the United States of America Y1 - 2012 A1 - Joanna I. Sulkowska A1 - Morcos, Faruck A1 - Weigt, Martin A1 - Hwa, Terence A1 - Onuchic, José N KW - Amino Acid Sequence KW - Genomics KW - Molecular Dynamics Simulation KW - Molecular Sequence Data KW - Proteins KW - Sequence Homology, Amino Acid AB - We introduce a theoretical framework that exploits the ever-increasing genomic sequence information for protein structure prediction. Structure-based models are modified to incorporate constraints by a large number of non-local contacts estimated from direct coupling analysis (DCA) of co-evolving genomic sequences. A simple hybrid method, called DCA-fold, integrating DCA contacts with an accurate knowledge of local information (e.g., the local secondary structure) is sufficient to fold proteins in the range of 1-3 Å resolution. VL - 109 IS - 26 ER - TY - JOUR T1 - How noise in force fields can affect the structural refinement of protein models? JF - Proteins Y1 - 2012 A1 - Pawel Gniewek A1 - Andrzej Koliński A1 - Robert L. Jernigan A1 - Andrzej Kloczkowski KW - force field KW - knowledge-based potentials KW - normal modes analysis KW - protein structure prediction KW - protein structure refinement KW - white noise AB - Structural refinement of predicted models of biological macromolecules using atomistic or coarse-grained molecular force fields having various degree of error is investigated. The goal of this analysis is to estimate what is the probability for designing an effective structural refinement based on computations of conformational energies using force field, and starting from a structure predicted from the sequence (using template-based or template-free modeling), and refining it to bring the structure into closer proximity to the native state. It is widely believed that it should be possible to develop such a successful structure refinement algorithm by applying an iterative procedure with stochastic sampling and appropriate energy function, which assesses the quality (correctness) of protein decoys. Here, an analysis of noise in an artificially introduced scoring function is investigated for a model of an ideal sampling scheme, where the underlying distribution of RMSDs is assumed to be Gaussian. Sampling of the conformational space is performed by random generation of RMSD values. We demonstrate that whenever the random noise in a force field exceeds some level, it is impossible to obtain reliable structural refinement. The magnitude of the noise, above which a structural refinement, on average is impossible, depends strongly on the quality of sampling scheme and a size of the protein. Finally, possible strategies to overcome the intrinsic limitations in the force fields for impacting the development of successful refinement algorithms are discussed. Proteins 2011;. © 2011 Wiley Periodicals, Inc. VL - 80 UR - http://www.ncbi.nlm.nih.gov/pubmed/22223184 ER - TY - JOUR T1 - Modeling Protein Structures and their Complexes with Sparse Experimental Data JF - From Computational Biophysics to Systems Biology (CBSB11) Proceedings Y1 - 2012 A1 - Dominik Gront A1 - Maciej Blaszczyk A1 - Jacek Wabik A1 - Andrzej Koliński AB - BioShell project has been started in 2005 as a set of stand-alone programs aimed on simplification of typical bioinformatics tasks. Since then it has evolved to become a fully featured scripting language for biomolecular modeling and structural bioinformatics. Most recently, the development of the package is focused on incorporating various types of experimental data into protocols for structure prediction of proteins and their complexes. In this work we present an application of Small Angle Xray Scattering (SAXS) profiles to the determination of mutual domain orientation in multi-domain proteins. Preliminary results suggest that the scattering data can be successfully used in studies of large macromolecular assemblies providing that the structure of the individual interacting partners are known. VL - 8 ER - TY - JOUR T1 - Modelowanie Molekularne Białek Błonowych (Molecular Modeling of Membrane Proteins) JF - Na pograniczu chemii i biologii (At the Treshold of Chemistry and Biology) vol. XXVIII, H. Koroniak, J. Barciszewski eds, Wydawnictwo Naukowe UAM, Poznań Y1 - 2012 A1 - Aleksandra Dawid A1 - Michal Kolinski A1 - Andrzej Koliński A1 - Sebastian Kmiecik AB - Jednym z głównych celów współczesnych badań biomedycznych jest zrozumienie na poziomie molekularnym podstawowych procesów odpowiedzialnych za prawidłowe funkcjonowanie organizmu, a także zachodzących w nim procesów chorobotwórczych. Kluczowym elementem wielu takich mechanizmów są białka błonowe (związane ze strukturą błon biologicznych). Szacuje się, że ponad 60% celów dla nowych leków to białka błonowe [1]. Ich zróżnicowana funkcjonalność przejawia się w wielu aspektach życia komórkowego: utrzymują stabilność strukturalną komórek, stanowią ważny element kaskad sygnalizacyjnych jako receptory błonowe, wykazują aktywność katalityczną występując w roli enzymów, są odpowiedzialne za transport molekularny małych cząsteczek przez błonę lipidową jako kanały, transportery oraz pompy jonowe. Na szczególną uwagę zasługuje rodzina A podobnych do rodopsyny (ang. rhodopsin-like) receptorów błonowych sprzężonych z białkami G (GPCR – ang. G protein-coupled receptors), odpowiedzialnych między innymi za kontrolę odczuwania bólu (receptory opioidowe), ciśnienia tętniczego (receptory adrenergiczne), proces widzenia (rodopsyna), czy odczuwanie smaku i zapachu. Ich wspólną funkcją jest przekazywanie oraz wzmacnianie specyficznych sygnałów docierających do wnętrza komórki z jej otoczenia. Mechanizm tego procesu rozpoczyna się od związania cząsteczki sygnałowej (liganda) przez zewnątrzkomórkową domenę receptora. Prowadzi to do zmian konformacyjnych w strukturze receptora umożliwiających wiązanie białek G po wewnętrznej stronie błony oraz ich aktywację. Aktywowane białka G mogą następnie przekazać sygnał do dalszych białek efektorowych zlokalizowanych we wnętrzu komórki, a tym samym zainicjować skomplikowane kaskady sygnalizacyjne. Pojedynczy receptor może aktywować wiele białek G co prowadzi do znacznego wzmocnienia przekazywanego sygnału. Wszelkie nieprawidłowości występujące na dowolnym etapie przekazywania sygnału mogą doprowadzić do zaburzenia fizjologii oraz inicjacji procesów chorobotwórczych [2,3]. Aby im przeciwdziałać, niezwykle pomocna jest znajomość mechanizmu działania danego receptora na poziomie molekularnym. Oznacza to konieczność znajomości struktury receptora (z dokładnością do położenia poszczególnych atomów), co jest pierwszym etapem w drodze do zrozumienia mechanizmu przeniesienia sygnału oraz stanowi punkt wyjściowy do projektowania nowych, bardziej skutecznych leków, które będą selektywne względem danego typu receptora. W porównaniu do białek globularnych, eksperymentalne otrzymywanie struktury białek błonowych jest dużo bardziej skomplikowanym zadaniem, często niewykonalnym przy obecnym stanie wiedzy. Jest to spowodowane problemami pojawiającymi się podczas procesu krystalizacji białek błonowych (duża powierzchnia hydrofobowa, środowisko błony, niestabilność konformacyjna, niski poziom ekspresji) [4,5]. Pomimo, że białka błonowe stanowią około jedną trzecią wszystkich białek obecnych w ludzkim genomie [6], zaledwie około 1% znanych struktur przestrzennych białek należy do przedstawicieli tej rodziny. Nieliczne, dostępne struktury krystalograficzne otrzymane w specyficznych warunkach (bez błony biologicznej) są niezwykle pomocne w badaniach mechanizmu działania tych białek. Biorąc pod uwagę ograniczenia metod eksperymentalnych oraz ogromne znaczenie białek błonowych dla przemysłu farmakologicznego, zastosowanie metod teoretycznych do badania ich struktury, dynamiki i funkcji jest bardzo obiecującą alternatywą. ER - TY - Generic T1 - Multiscale Approach to Thermodynamics and Dynamics of a beta-Hairpin Folding T2 - From Computational Biophysics to Systems Biology (CBSB11) Proceedings Y1 - 2012 A1 - Jacek Wabik A1 - Dominik Gront A1 - Sebastian Kmiecik A1 - Andrzej Koliński AB - Formation of the beta-hairpin is the first step along the 2GB1 protein folding pathway. This -structure is one of the nuclei during this process and controls the rate of the whole protein folding. We present an attempt to improve the Replica ExchangeMolecular Dynamics (REMD) by utilising the output structures from the coarse-grainedMonte Carlo dynamics as the input for the all-atom REMD. This approach enables effective sampling and can be helpful in elucidating the mechanisms of beta-hairpin folding. Thermodynamics and dynamics is analyzed focusing on the number of native contacts during simulations. The energy landscape is analyzed by means of the Histogram Method. JF - From Computational Biophysics to Systems Biology (CBSB11) Proceedings VL - 8 UR - http://biocomp.chem.uw.edu.pl/pdf/430\_Wabik\_BHairpin\_folding\_CBSB11Proceed\_2012.pdf ER - TY - JOUR T1 - Optimization of profile-to-profile alignment parameters for one-dimensional threading JF - Journal of Computational Biology Y1 - 2012 A1 - Pawel Gniewek A1 - Andrzej Koliński A1 - Dominik Gront AB - The development of automatic approaches for the comparison of protein sequences has become increasingly important. Methods that compare profiles allow for the use of information about whole protein families, resulting in more sensitive and accurate detection of distantly related sequences. In this contribution, we describe a thorough optimization and tests of a profile-to-profile alignment method. A number of different scoring schemes has been implemented and compared on the basis of their ability to identify a template protein from the same SCOP family as a query. In addition to sequence profiles, secondary structure profiles were used to increase the rate of successful detection. Our results show that a properly tuned one-dimensional threading method can recognize a correct template from the same SCOP family nearly as well as structural alignment. Our benchmark set, which might be useful in other similar studies, as well as the fold-recognition software we developed may be downloaded (www.bioshell.pl/profile-alignments). VL - 19 UR - http://www.ncbi.nlm.nih.gov/pubmed/22731622 ER - TY - JOUR T1 - Optimization of protein models JF - Wiley Interdisciplinary Reviews: Computational Molecular Science Y1 - 2012 A1 - Dominik Gront A1 - Sebastian Kmiecik A1 - Maciej Blaszczyk A1 - Dariusz Ekonomiuk A1 - Andrzej Koliński AB - Protein structure predictions, and experimentally derived protein structures, very often require certain structure improvement (refinement), which means bringing it closer to real, usually in vivo working conformations. In respect to the variety of protein models to be refined, computational optimization procedures could be divided into localized (applied to a small part of a structure) and global (whole structure). Generally speaking, the first problem is usually tractable, and the latter remains to be extremely challenging for systems larger then peptides or small proteins: optimization complexity and difficulty dramatically increase with the size of structures to be optimized. VL - 2 UR - http://doi.wiley.com/10.1002/wcms.1090 ER - TY - JOUR T1 - An Optimized Replica Exchange Molecular Dynamics Approach JF - From Computational Biophysics to Systems Biology (CBSB11) Proceedings Y1 - 2012 A1 - Maksim Kouza A1 - Ulrich H. E. Hansmann VL - 8 ER - TY - Generic T1 - Prediction of Experimental Phi Values in Protein Folding by Simulation with Knowledge-based Potentials: B Domain of Protein A T2 - From Computational Biophysics to Systems Biology (CBSB11) Proceedings Y1 - 2012 A1 - Sebastian Kmiecik A1 - Maciej Blaszczyk A1 - Andrzej Koliński AB - Here we highlight our recent studies which showed that simulation of protein folding process, with the use of knowledge-based potentials and reduced representation of the polypeptide chain, can be a useful method in prediction of experimental Phi values. Apart from providing hints for experimental design, the simulation method (by delivering trajectory of conformations) enables interpretation of the Phi values. The interpretation is a non-trivial task, especially as the obtaining of reliable Phi values is not-trivial either. Here, we present a protein chain mobility profile, from simulation of B domain of protein A, consistent with a detailed Phi value analysis. JF - From Computational Biophysics to Systems Biology (CBSB11) Proceedings VL - 8 ER - TY - Generic T1 - Protein Structure Prediction Using CABS – A Consensus Approach T2 - From Computational Biophysics to Systems Biology (CBSB11) Proceedings Y1 - 2012 A1 - Maciej Blaszczyk A1 - Michal Jamroz A1 - Dominik Gront A1 - Andrzej Koliński AB - We have designed a new pipeline for protein structure prediction based on the CABS engine. The procedure is fully automated and generates consensus models from a set of templates. Restraints derived from the templates define a region of conformational space, which is then sampled by Replica Exchange Monte Carlo algorithm implemented in CABS. Results from CASP9 show, that for great majority of targets this approach leads to better models than the mean quality of templates (in respect to GDT TS). In five cases the obtained models were the best among all predictions submitted to CASP9 as the first models. JF - From Computational Biophysics to Systems Biology (CBSB11) Proceedings VL - 8 ER - TY - JOUR T1 - Structural features that predict real-value fluctuations of globular proteins JF - Proteins Y1 - 2012 A1 - Michal Jamroz A1 - Andrzej Koliński A1 - Daisuke Kihara KW - fluctuation prediction KW - molecular dynamics KW - protein dynamics KW - protein flexibility KW - structure-dynamics relationship KW - support vector regression AB - It is crucial to consider dynamics for understanding the biological function of proteins. We used a large number of molecular dynamics (MD) trajectories of nonhomologous proteins as references and examined static structural features of proteins that are most relevant to fluctuations. We examined correlation of individual structural features with fluctuations and further investigated effective combinations of features for predicting the real value of residue fluctuations using the support vector regression (SVR). It was found that some structural features have higher correlation than crystallographic B-factors with fluctuations observed in MD trajectories. Moreover, SVR that uses combinations of static structural features showed accurate prediction of fluctuations with an average Pearson's correlation coefficient of 0.669 and a root mean square error of 1.04 \AA. This correlation coefficient is higher than the one observed in predictions by the Gaussian network model (GNM). An advantage of the developed method over the GNMs is that the former predicts the real value of fluctuation. The results help improve our understanding of relationships between protein structure and fluctuation. Furthermore, the developed method provides a convienient practial way to predict fluctuations of proteins using easily computed static structural features of proteins. VL - 80 UR - http://www.ncbi.nlm.nih.gov/pubmed/22328193 ER - TY - JOUR T1 - The unique cysteine knot regulates the pleotropic hormone leptin. JF - PLoS One Y1 - 2012 A1 - Haglund, Ellinor A1 - Joanna I. Sulkowska A1 - He, Zhao A1 - Feng, Gen-Sheng A1 - Jennings, Patricia A A1 - Onuchic, José N KW - Cysteine KW - Humans KW - Kinetics KW - Leptin KW - MCF-7 Cells KW - Models, Molecular KW - Oxidation-Reduction KW - Signal Transduction AB - Leptin plays a key role in regulating energy intake/expenditure, metabolism and hypertension. It folds into a four-helix bundle that binds to the extracellular receptor to initiate signaling. Our work on leptin revealed a hidden complexity in the formation of a previously un-described, cysteine-knotted topology in leptin. We hypothesized that this unique topology could offer new mechanisms in regulating the protein activity. A combination of in silico simulation and in vitro experiments was used to probe the role of the knotted topology introduced by the disulphide-bridge on leptin folding and function. Our results surprisingly show that the free energy landscape is conserved between knotted and unknotted protein, however the additional complexity added by the knot formation is structurally important. Native state analyses led to the discovery that the disulphide-bond plays an important role in receptor binding and thus mediate biological activity by local motions on distal receptor-binding sites, far removed from the disulphide-bridge. Thus, the disulphide-bridge appears to function as a point of tension that allows dissipation of stress at a distance in leptin. VL - 7 IS - 9 ER - TY - JOUR T1 - 13,13-Dimethyl-des-C,D analogues of (20S)-1α,25-dihydroxy-2-methylene-19-norvitamin D₃ (2MD): total synthesis, docking to the VDR, and biological evaluation JF - Bioorganic & Medicinal Chemistry Y1 - 2011 A1 - Katarzyna Plonska-Ocypa A1 - Izabela Sibilska A1 - Rafal R. Sicinski A1 - Wanda Sicinska A1 - Lori A. Plum A1 - Hector F. DeLuca KW - Animals KW - Calcitriol KW - Cell Differentiation KW - Crystallography, X-Ray KW - HL-60 Cells KW - Humans KW - Male KW - Models, Molecular KW - Molecular Conformation KW - Rats KW - Receptors, Calcitriol KW - Structure-Activity Relationship AB - As a continuation of our studies focused on the vitamin D compounds lacking the C,D-hydrindane system, 13,13-dimethyl-des-C,D analogues of (20S)-1α,25-dihydroxy-2-methylene-19-norvitamin D(3) (2, 2MD) were prepared by total synthesis. The known cyclohexanone 30, a precursor of the desired A-ring phosphine oxide 11, was synthesized starting with the keto acetal 13, whereas the aldehyde 12, constituting an acyclic 'upper' building block, was obtained from the isomeric esters 34, prepared previously in our laboratory. The commercial 1,4-cyclohexanedione monoethylene ketal (13) was enantioselectively α-hydroxylated utilizing the α-aminoxylation process catalyzed by l-proline, and the introduced hydroxy group was protected as a TBS, TPDPS, and SEM ether. Then the keto group in the obtained compounds 15-17 was methylenated and the allylic hydroxylation was performed with selenium dioxide and pyridine N-oxide. After separation of the isomers, the newly introduced hydroxy group was protected and the ketal group hydrolyzed to yield the corresponding protected (3R,5R)-3,5-dihydroxycyclohexanones 30-32. The esters 34, starting compounds for the C,D-fragment 12, were first α-methylated, then reduced and the resulted primary alcohols 36 were deoxygenated using the Barton-McCombie protocol. Primary hydroxy group in the obtained diether 38 was deprotected and oxidized to furnish the aldehyde 12. The Wittig-Horner coupling of the latter with the anion of the phosphine oxide 11, followed by hydroxyl deprotection furnished two isomeric 13,13-dimethyl-des-C,D analogues of 2MD (compounds 10 and 42) differing in configuration of their 7,8-double bond. Pure vitamin D analogues were isolated by HPLC and their biological activity was examined. The in vitro tests indicated that, compared to the analogue 7, unsubstituted at C-13, the synthesized vitamin D analogue 10 showed markedly improved VDR binding ability, significantly enhanced HL-60 differentiation activity as well as increased transcriptional potency. Docking simulations provided a rational explanation for the observed binding affinity of these ligands to the VDR. Biological in vivo tests proved that des-C,D compound 10 retained some intestinal activity. Its geometrical isomer 42 was devoid of any biological activity. VL - 19 IS - 23 ER - TY - JOUR T1 - Analysis and optimization of interactions between peptides mimicking the GD2 ganglioside and the monoclonal antibody 14G2a JF - International Journal of Molecular Medicine Y1 - 2011 A1 - Irena Horwacik A1 - Mateusz Kurcinski A1 - Malgorzata Bzowska A1 - Aleksandra K. Kowalczyk A1 - Dominik Czaplicki A1 - Andrzej Koliński A1 - Hanna Rokita KW - Amino Acid Sequence KW - Antibodies KW - Binding Sites KW - Cell Line KW - Gangliosides KW - Gangliosides: immunology KW - Humans KW - Models KW - Molecular KW - Molecular Mimicry KW - Molecular Sequence Data KW - Monoclonal KW - Monoclonal: chemistry KW - Monoclonal: immunology KW - Neuroblastoma KW - Neuroblastoma: genetics KW - Neuroblastoma: immunology KW - Peptide Library KW - Peptides KW - Peptides: chemistry KW - Peptides: immunology KW - Structure-Activity Relationship KW - Tumor AB -

Overexpression of the GD2 ganglioside (GD2) is a hallmark of neuroblastoma. The antigen is used in neuroblastoma diagnosis and to target newly developed therapies to cancer cells. Peptide mimetics are novel approaches in the design of antigens for vaccine development. We previously reported the isolation of five GD2-mimicking peptides from the LX-8 phage display library with the monoclonal antibody (mAb) 14G2a. The goal of our current study was to analyze and optimize the binding of the peptide mimetics to the mAb 14G2a. Therefore, we performed further experiments and supported them with molecular modeling to investigate structure-activity relationships that are the basis for the observed mimicry of GD2 by our peptides. Here, we show that the peptides have overlapping binding sites on the mAb, 14G2a and restricted specificity, as they did not crossreact with other ganglioside-specific antibodies tested. In addition we demonstrate that the phage environment was involved in the process of selection of our peptides. The AAEGD sequence taken from the viral major coat protein, p8, and added to the C-termini of the peptides \#65, \#85 and \#94 significantly improved their binding to the mAb, 14G2a. By application of analogs with amino acid substitutions and sequence truncations, we elucidated the structure-activity relationships necessary for the interactions between the 14G2a mAb and the peptide \#94 (RCNPNMEPPRCF). We identified amino acids indispensable for the observed GD2-mimicry by \#94 and confirmed a pivotal role of the disulphide bridge between the cysteine residues of \#94 for binding to the mAb 14G2a. More importantly, we report five new peptides demonstrating a significant improvement of mAb 14G2a binding. The experimental data were supported and expanded with molecular modeling tools. Taken together, the experimental results and the in silico data allowed us to probe in detail the mechanism of the molecular mimicry of GD2 by the peptides. Additionally, we significantly optimized binding of the leading peptide sequence \#94 to the mAb 14G2a. We can conclude that our findings add to the knowledge on factors governing selections of peptide mimetics from phage-display libraries.

VL - 28 UR - http://www.ncbi.nlm.nih.gov/pubmed/21455557 ER - TY - JOUR T1 - BSDB: the biomolecule stretching database. JF - Nucleic Acids Research Y1 - 2011 A1 - Sikora, Mateusz A1 - Joanna I. Sulkowska A1 - Witkowski, Bartlomiej S A1 - Cieplak, Marek KW - Biomechanical Phenomena KW - Databases, Protein KW - Models, Chemical KW - Molecular Dynamics Simulation KW - Protein Structure, Secondary KW - Proteins AB - We describe the Biomolecule Stretching Data Base that has been recently set up at http://www.ifpan.edu.pl/BSDB/. It provides information about mechanostability of proteins. Its core is based on simulations of stretching of 17 134 proteins within a structure-based model. The primary information is about the heights of the maximal force peaks, the force-displacement patterns, and the sequencing of the contact-rupturing events. We also summarize the possible types of the mechanical clamps, i.e. the motifs which are responsible for a protein's resistance to stretching. VL - 39 IS - Database issue ER - TY - JOUR T1 - CABS-NMR–De novo tool for rapid global fold determination from chemical shifts, residual dipolar couplings and sparse methyl-methyl NOEs JF - Journal of c\Computational Chemistry Y1 - 2011 A1 - Dorota Latek A1 - Andrzej Koliński KW - Algorithms KW - Animals KW - Cattle KW - Magnetic Resonance Spectroscopy KW - Magnetic Resonance Spectroscopy: methods KW - Models KW - Molecular KW - Monte Carlo Method KW - Protein Conformation KW - Protein Folding KW - Proteins KW - Proteins: chemistry KW - S100 Proteins KW - S100 Proteins: chemistry AB - Recent development of nuclear magnetic resonance (NMR) techniques provided new types of structural restraints that can be successfully used in fast and low-cost global protein fold determination. Here, we present CABS-NMR, an efficient protein modeling tool, which takes advantage of such structural restraints. The restraints are converted from original NMR data to fit the coarse grained protein representation of the C-Alpha-Beta-Side-group (CABS) algorithm. CABS is a Monte Carlo search algorithm that uses a knowledge-based force field. Its versatile structure enables a variety of protein-modeling protocols, including purely de novo folding, folding guided by restraints derived from template structures or, structure assembly based on experimental data. In particular, CABS-NMR uses the distance and angular restraints set derived from various NMR experiments. This new modeling technique was successfully tested in structure determination of 10 globular proteins of size up to 216 residues, for which sparse NMR data were available. Additional detailed analysis was performed for a S100A1 protein. Namely, we successfully predicted Nuclear Overhauser Effect signals on the basis of low-energy structures obtained from chemical shifts by CABS-NMR. It has been observed that utility of chemical shifts and other types of experimental data (i.e. residual dipolar couplings and methyl-methyl Nuclear Overhauser Effect signals) in the presented modeling pipeline depends mainly on size of a protein and complexity of its topology. In this work, we have provided tools for either post-experiment processing of various kinds of NMR data or fast and low-cost structural analysis in the still challenging field of new fold predictions. VL - 32 UR - http://www.ncbi.nlm.nih.gov/pubmed/20806263 ER - TY - JOUR T1 - Computational study of binding of epothilone A to β-tubulin JF - Acta Biochimica Polonica Y1 - 2011 A1 - Karol Kamel A1 - Andrzej Koliński KW - Animals KW - Binding Sites KW - Cattle KW - Computer Simulation KW - Epothilones KW - Epothilones: chemistry KW - Hydrogen Bonding KW - Models KW - Molecular KW - Protein Binding KW - Thermodynamics KW - Tubulin KW - Tubulin: chemistry AB - Understanding the interactions of epothilones with β-tubulin is crucial for computer aided rational design of macrocyclic drugs based on epothilones and epothilone derivatives. Despite numerous structure-activity relationship investigations we still lack substantial knowledge about the binding mode of epothilones and their derivatives to β-tubulin. In this work, we reevaluated the electron crystallography structure of epothilone A/β-tubulin complex (PDB entry 1TVK) and proposed an alternative binding mode of epothilone A to β-tubulin that explains more experimental facts. VL - 58 UR - http://www.ncbi.nlm.nih.gov/pubmed/21633729 ER - TY - Generic T1 - Human telomerase model shows the role of the TEN domain in advancing the double helix for the next polymerization step T2 - Proceedings of the National Academy of Sciences of the United States of America Y1 - 2011 A1 - Kamil Steczkiewicz A1 - Michael T. Zimmermann A1 - Mateusz Kurcinski A1 - Benjamin A. Lewis A1 - Drena Dobbs A1 - Andrzej Kloczkowski A1 - Robert L. Jernigan A1 - Andrzej Koliński A1 - Krzysztof Ginalski KW - Amino Acid KW - Amino Acid Sequence KW - Binding Sites KW - Binding Sites: genetics KW - Catalytic Domain KW - Computer Simulation KW - DNA KW - DNA: chemistry KW - DNA: genetics KW - DNA: metabolism KW - Humans KW - Kinetics KW - Models KW - Molecular KW - Molecular Sequence Data KW - Nucleic Acid Conformation KW - Nucleic Acid Heteroduplexes KW - Nucleic Acid Heteroduplexes: chemistry KW - Nucleic Acid Heteroduplexes: genetics KW - Nucleic Acid Heteroduplexes: metabolism KW - Polymerization KW - Protein Binding KW - Protein Structure KW - RNA KW - RNA: chemistry KW - RNA: genetics KW - RNA: metabolism KW - Secondary KW - Sequence Homology KW - Telomerase KW - Telomerase: chemistry KW - Telomerase: genetics KW - Telomerase: metabolism KW - Telomere KW - Telomere: chemistry KW - Telomere: genetics KW - Telomere: metabolism KW - Tertiary AB - Telomerases constitute a group of specialized ribonucleoprotein enzymes that remediate chromosomal shrinkage resulting from the "end-replication" problem. Defects in telomere length regulation are associated with several diseases as well as with aging and cancer. Despite significant progress in understanding the roles of telomerase, the complete structure of the human telomerase enzyme bound to telomeric DNA remains elusive, with the detailed molecular mechanism of telomere elongation still unknown. By application of computational methods for distant homology detection, comparative modeling, and molecular docking, guided by available experimental data, we have generated a three-dimensional structural model of a partial telomerase elongation complex composed of three essential protein domains bound to a single-stranded telomeric DNA sequence in the form of a heteroduplex with the template region of the human RNA subunit, TER. This model provides a structural mechanism for the processivity of telomerase and offers new insights into elongation. We conclude that the RNADNA heteroduplex is constrained by the telomerase TEN domain through repeated extension cycles and that the TEN domain controls the process by moving the template ahead one base at a time by translation and rotation of the double helix. The RNA region directly following the template can bind complementarily to the newly synthesized telomeric DNA, while the template itself is reused in the telomerase active site during the next reaction cycle. This first structural model of the human telomerase enzyme provides many details of the molecular mechanism of telomerase and immediately provides an important target for rational drug design. JF - Proceedings of the National Academy of Sciences of the United States of America VL - 108 UR - http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3111281&tool=pmcentrez&rendertype=abstract ER - TY - CHAP T1 - Lattice polymers and protein models T2 - Multiscale Approaches to Protein Modeling Y1 - 2011 A1 - Andrzej Koliński A1 - Andrzej Koliński AB - The size of conformational space of chain polymers is enormous. Much has been learned about polymer structure, thermodynamics, and dynamics by theoretical considerations and numerical study of simple lattice models. Self-avoiding random walks on a lattice provide a good approximation for the excluded volume effect and nature of the coil–globule transition. Semiflexible polymers on a lattice exhibit two-state collapse transition that captures some essential features of the all-or-none folding transition of small globular proteins. More complex, decorated with some structural details, lattice polymers provide a very powerful means for study of protein dynamics and thermodynamics and protein structure prediction. JF - Multiscale Approaches to Protein Modeling PB - Springer CY - New York ER - TY - JOUR T1 - Multibody coarse-grained potentials for native structure recognition and quality assessment of protein models JF - Proteins Y1 - 2011 A1 - Pawel Gniewek A1 - Sumudu P. Leelananda A1 - Andrzej Koliński A1 - Robert L. Jernigan A1 - Andrzej Kloczkowski KW - Amino Acids KW - Amino Acids: chemistry KW - Computational Biology KW - Computational Biology: methods KW - Models KW - Molecular KW - Protein Conformation KW - Proteins KW - Proteins: chemistry AB - Multibody potentials have been of much interest recently because they take into account three dimensional interactions related to residue packing and capture the cooperativity of these interactions in protein structures. Our goal was to combine long range multibody potentials and short range potentials to improve recognition of native structure among misfolded decoys. We optimized the weights for four-body nonsequential, four-body sequential, and short range potentials to obtain optimal model ranking results for threading and have compared these data against results obtained with other potentials (26 different coarse-grained potentials from the Potentials 'R'Us web server have been used). Our optimized multibody potentials outperform all other contact potentials in the recognition of the native structure among decoys, both for models from homology template-based modeling and from template-free modeling in CASP8 decoy sets. We have compared the results obtained for this optimized coarse-grained potentials, where each residue is represented by a single point, with results obtained by using the DFIRE potential, which takes into account atomic level information of proteins. We found that for all proteins larger than 80 amino acids our optimized coarse-grained potentials yield results comparable to those obtained with the atomic DFIRE potential. VL - 79 UR - http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3093657&tool=pmcentrez&rendertype=abstract ER - TY - CHAP T1 - Multiscale approach to protein folding dynamics T2 - Multiscale Approaches to Protein Modeling Y1 - 2011 A1 - Sebastian Kmiecik A1 - Michal Jamroz A1 - Andrzej Koliński A1 - Andrzej Koliński KW - coarse-grained modeling KW - Molecular Dynamics Simulation KW - protein dynamics AB - Dynamic behavior of proteins is a key factor for understanding the functions of a living cell. Description of the conformational transitions of proteins remains extremely difficult for the computational simulation as well as the experimental techniques. No technique is able to span extremely short dynamic events together with long-timescale processes when the most interesting transitions occur. Thus new methods for simulation and utilization of all accessible experimental data are needed. The advances in the development of hybrid models, which attempt to combine a simplified modeling efficiency with atomic resolution accuracy, should provide new opportunities for the use of computer simulation in the integration of different kinds of data to study folding dynamics at relevant timescales. This review outlines the advances in description of protein dynamics and discusses recent applications of the CABS-reduced modeling tool to the studies of protein folding dynamics. JF - Multiscale Approaches to Protein Modeling PB - Springer CY - New York ER - TY - CHAP T1 - Multiscale protein and peptide docking T2 - Multiscale Approaches to Protein Modeling Y1 - 2011 A1 - Mateusz Kurcinski A1 - Michal Jamroz A1 - Andrzej Koliński AB - The number of functional protein complexes in a cell is larger by an order of magnitude than the number of proteins. The experimentally determined three-dimensional structures exist for only a very small fraction of these complexes. Thus, the methods for theoretical prediction of structures of protein assemblies are extremely important for molecular biology. Association of two (or more proteins) always induces conformational changes of the individual components. In many cases, these induced changes are relatively small and involve mostly the side chains at the association interface. In such cases, the approaches of rigid-body docking of two (or more) structures are quite successful. Quite frequently, however, the docking-induced conformational changes are significant. In such cases, prediction of the resulting structures is extremely challenging. The cases, where experimental structures of some components do not exist, are yet even more difficult. In this chapter, we briefly overview the existing in silico docking methods and describe a multiscale strategy of unrestricted flexible docking of proteins and peptides. JF - Multiscale Approaches to Protein Modeling PB - Springer CY - New York ER - TY - JOUR T1 - Note: A simple picture of subdiffusive polymer motion from stochastic simulations JF - The Journal of Chemical Physics Y1 - 2011 A1 - Pawel Gniewek A1 - Andrzej Koliński VL - 134 UR - http://www.ncbi.nlm.nih.gov/pubmed/21303171 ER - TY - CHAP T1 - Preface T2 - Multiscale Approaches to Protein Modeling Y1 - 2011 A1 - Andrzej Koliński A1 - Andrzej Koliński JF - Multiscale Approaches to Protein Modeling PB - Springer CY - New York ER - TY - JOUR T1 - Simulation of chaperonin effect on protein folding: a shift from nucleation-condensation to framework mechanism JF - Journal of the American Chemical Society Y1 - 2011 A1 - Sebastian Kmiecik A1 - Andrzej Koliński KW - Chaperonins KW - Chaperonins: metabolism KW - Computational Biology KW - Models KW - Molecular KW - Protein Conformation KW - protein dynamics KW - Protein Folding KW - Protein Structure KW - Staphylococcal Protein A KW - Staphylococcal Protein A: chemistry KW - Staphylococcal Protein A: metabolism KW - Stochastic Processes KW - Tertiary AB -

The iterative annealing mechanism (IAM) of chaperonin-assisted protein folding is explored in a framework of a well-established coarse-grained protein modeling tool, which enables the study of protein dynamics in a time-scale well beyond classical all-atom molecular mechanics. The chaperonin mechanism of action is simulated for two paradigm systems of protein folding, B domain of protein A (BdpA) and B1 domain of protein G (GB1), and compared to chaperonin-free simulations presented here for BdpA and recently published for GB1. The prediction of the BdpA transition state ensemble (TSE) is in perfect agreement with experimental findings. It is shown that periodic distortion of the polypeptide chains by hydrophobic chaperonin interactions can promote rapid folding and leads to a decrease in folding temperature. It is also demonstrated how chaperonin action prevents kinetically trapped conformations and modulates the observed folding mechanisms from nucleation-condensation to a more framework-like.

VL - 133 UR - http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3132998&tool=pmcentrez&rendertype=abstract ER - TY - JOUR T1 - Universal geometrical factor of protein conformations as a consequence of energy minimization JF - EPL (Europhysics Letters) Y1 - 2011 A1 - Ming-Chya Wu A1 - Mai Suan Li A1 - Wen-Jong Ma A1 - Maksim Kouza A1 - Chin-Kun Hu VL - 96:68005 doi: 10.1209/0295-5075/96/68005 ER - TY - JOUR T1 - Velocity scaling for optimizing replica exchange molecular dynamics JF - The Journal of Chemical Physics Y1 - 2011 A1 - Maksim Kouza A1 - Ulrich H. E. Hansmann KW - biological techniques KW - biology computing KW - molecular biophysics KW - Proteins KW - replica techniques AB - We discuss the use of velocity rescaling for generating rejection-free exchange moves in replica exchange molecular dynamics. We test the efficiency of this approach for a common test case, the trp-cage protein. Advantages and limitations of the approach are discussed and possible extensions outlined. PB - AIP VL - 134 UR - http://link.aip.org/link/?JCP/134/044124/1 ER - TY - JOUR T1 - Coarse-grained Monte Carlo simulations of mucus: structure, dynamics, and thermodynamics JF - Biophysical Journal Y1 - 2010 A1 - Pawel Gniewek A1 - Andrzej Koliński KW - Cysteine KW - Cysteine: chemistry KW - Diffusion KW - Gels KW - Humans KW - Hydrophobic and Hydrophilic Interactions KW - Molecular Dynamics Simulation KW - Monte Carlo Method KW - Mucins KW - Mucins: chemistry KW - Mucus KW - Mucus: chemistry KW - Protein Structure KW - Tertiary KW - Thermodynamics AB - A simple coarse-grained model of mucus structure and dynamics is proposed and evaluated. The model is based on simple cubic, face-centered lattice representation. Mucins are simulated as lattice chains in which each bead of the model chains represents a mucin domain, equivalent to its Kuhn segment. The remaining lattice sites are considered to be occupied by the solvent. Model mucins consist of three types of domains: polar (glycosylated central segments), hydrophobic, and cysteine-rich, located at the terminal part of the mucin chains. The sequence of these domains mimics the sequence of real mucins. Static and dynamic properties of the system were studied by means of Monte Carlo dynamics. It was shown that the model system undergoes sol-gel transition and that the interactions between hydrophobic domains are responsible for the transition and characteristic properties of the dynamic network in the gel phase. Cysteine-rich domains are essential for frictional properties of the system. Structural and dynamic properties of the model mucus observed in simulations are in qualitative agreement with known experimental facts and provide mechanistic explanation of complex properties of real mucus. PB - Biophysical Society VL - 99 UR - http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2998598&tool=pmcentrez&rendertype=abstract ER - TY - JOUR T1 - Mechanical unfolding of acylphosphatase studied by single-molecule force spectroscopy and MD simulations JF - Biophys J Y1 - 2010 A1 - G. Arad-Haase A1 - S.G. Chuartzman A1 - S. Dagan A1 - R. Nevo A1 - Maksim Kouza A1 - B. K. Mai A1 - H.T. Nguyen A1 - M.S. Li A1 - Z. Reich AB - Single-molecule manipulation methods provide a powerful means to study protein transitions. Here we combined single-molecule force spectroscopy and steered molecular-dynamics simulations to study the mechanical properties and unfolding behavior of the small enzyme acylphosphatase (AcP). We find that mechanical unfolding of AcP occurs at relatively low forces in an all-or-none fashion and is decelerated in the presence of a ligand, as observed in solution measurements. The prominent energy barrier for the transition is separated from the native state by a distance that is unusually long for alpha/beta proteins. Unfolding is initiated at the C-terminal strand (beta(T)) that lies at one edge of the beta-sheet of AcP, followed by unraveling of the strand located at the other. The central strand of the sheet and the two helices in the protein unfold last. Ligand binding counteracts unfolding by stabilizing contacts between an arginine residue (Arg-23) and the catalytic loop, as well as with beta(T) of AcP, which renders the force-bearing units of the protein resistant to force. This stabilizing effect may also account for the decelerated unfolding of ligand-bound AcP in the absence of force. VL - 99 ER - TY - JOUR T1 - Modeling of loops in proteins: a multi-method approach JF - BMC Structural Biology Y1 - 2010 A1 - Michal Jamroz A1 - Andrzej Koliński KW - Databases KW - Models KW - Molecular KW - Protein KW - Protein Structure KW - Proteins KW - Proteins: chemistry KW - Software KW - Tertiary AB - BACKGROUND: Template-target sequence alignment and loop modeling are key components of protein comparative modeling. Short loops can be predicted with high accuracy using structural fragments from other, not necessairly homologous proteins, or by various minimization methods. For longer loops multiscale approaches employing coarse-grained de novo modeling techniques should be more effective. RESULTS: For a representative set of protein structures of various structural classes test predictions of loop regions have been performed using MODELLER, ROSETTA, and a CABS coarse-grained de novo modeling tool. Loops of various length, from 4 to 25 residues, were modeled assuming an ideal target-template alignment of the remaining portions of the protein. It has been shown that classical modeling with MODELLER is usually better for short loops, while coarse-grained de novo modeling is more effective for longer loops. Even very long missing fragments in protein structures could be effectively modeled. Resolution of such models is usually on the level 2-6 A, which could be sufficient for guiding protein engineering. Further improvement of modeling accuracy could be achieved by the combination of different methods. In particular, we used 10 top ranked models from sets of 500 models generated by MODELLER as multiple templates for CABS modeling. On average, the resulting molecular models were better than the models from individual methods. CONCLUSIONS: Accuracy of protein modeling, as demonstrated for the problem of loop modeling, could be improved by the combinations of different modeling techniques. VL - 10 UR - http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2837870&tool=pmcentrez&rendertype=abstract ER - TY - JOUR T1 - MSITE: a new computational tool for comparison of homological proteins in holo form JF - The Journal of Steroid Biochemistry and Molecular Biology Y1 - 2010 A1 - Wanda Sicinska A1 - Mateusz Kurcinski KW - Algorithms KW - Amino Acid Sequence KW - Amino Acids KW - Animals KW - Computational Biology KW - DNA Mutational Analysis KW - Humans KW - Ligands KW - Molecular Sequence Data KW - Protein Binding KW - Rats KW - Receptors, Calcitriol KW - Sequence Homology, Amino Acid KW - Software KW - Zebrafish AB - The mechanism by which nuclear receptors respond differentially to structurally distinct agonists is not a well understood process. However, it is now obvious that transcriptional activity of nuclear receptors is a function of their interactions with co-activators. Recently, we released a new computational tool, CCOMP, for comparing side chain conformations in crystal structures of homologous protein complexes. Application of the CCOMP program revealed that 20-epi-1alpha,25-(OH)2D3 changes the side chain conformation of vitamin D receptor amino acids residing mostly far away from the ligand-receptor contacts. This strongly suggests that the ligand-co-activator signaling pathway involves indirect interactions between amino acids lining the binding pocket and outer surface residues that could attract co-activators. To facilitate identification of amino acids transmitting the subtle receptor changes upon ligand/modulator binding we developed another simple tool, MSITE. The program automatically lists the nearest neighbors of a given amino acid (for example neighbors of residues that are in contact with a ligand or reorient their side chains in the presence of a co-factor) in an arbitrary number of compared complexes. Comparison of seven binary vitamin D receptor complexes holding as ligands the analogs of 1alpha,25-(OH)2D3 with inverted configuration at carbon 14 or 20, or with incorporated oxolane ring bridging carbons 20 and 23, is reported. VL - 121 IS - 1-2 ER - TY - JOUR T1 - A numerical investigation into possible mechanisms by that the A629P mutant of ATP7A causes Menkes Disease JF - Phys Chem Chem Phys Y1 - 2010 A1 - Maksim Kouza A1 - S. Gowtham A1 - M. Seel A1 - Ulrich H. E. Hansmann AB - We study in silico possible mechanisms by that the A629P mutant of ATP7A causes Menkes Disease. Our results indicate that the mutation does not have appreciable affects on the stability of copper-bound states but rather destabilizes the characteristic end-to-end β-sheet. In this way, the mutation presumably increases the probability for aggregation and/or degradation leading to decreased concentration of the monomer. VL - 12 ER - TY - Generic T1 - Protein secondary structure prediction using knowledge-based potentials T2 - International Conference on Fuzzy Computation and 2nd International Conference on Neural Computation Y1 - 2010 A1 - Saras Saraswathi A1 - Robert L. Jernigan A1 - Andrzej Kloczkowski A1 - Andrzej Koliński JF - International Conference on Fuzzy Computation and 2nd International Conference on Neural Computation ER - TY - JOUR T1 - Relationship between population of the fibril-prone conformation in the monomeric state and oligomer formation times of peptides: Insights from all-atom simulations JF - The Journal of Chemical Physics Y1 - 2010 A1 - Hoang Bao Nam A1 - Maksim Kouza A1 - Hoang Zung A1 - Mai Suan Li KW - aggregation KW - biochemistry KW - diseases KW - macromolecules KW - molecular biophysics KW - Proteins KW - self-assembly AB - Despite much progress in understanding the aggregation process of biomolecules, the factors that govern its rates have not been fully understood. This problem is of particular importance since many conformational diseases such as Alzheimer, Parkinson, and type-II diabetes are associated with the protein oligomerization. Having performed all-atom simulations with explicit water and various force fields for two short peptides KFFE and NNQQ, we show that their oligomer formation times are strongly correlated with the population of the fibril-prone conformation in the monomeric state. The larger the population the faster the aggregation process. Our result not only suggests that this quantity plays a key role in the self-assembly of polypeptide chains but also opens a new way to understand the fibrillogenesis of biomolecules at the monomeric level. The nature of oligomer ordering of NNQQ is studied in detail. PB - AIP VL - 132 UR - http://link.aip.org/link/?JCP/132/165104/1 ER - TY - JOUR T1 - Slipknotting upon native-like loop formation in a trefoil knot protein. JF - Proceedings of the National Academy of Sciences of the United States of America Y1 - 2010 A1 - Noel, Jeffrey K A1 - Joanna I. Sulkowska A1 - Onuchic, José N KW - Algorithms KW - Archaea KW - Archaeal Proteins KW - Crystallization KW - Databases, Protein KW - Models, Molecular KW - Molecular Dynamics Simulation KW - Protein Conformation KW - Protein Folding KW - Protein Multimerization KW - Protein Structure, Secondary KW - Protein Structure, Tertiary KW - Thermodynamics AB - Protein knots and slipknots, mostly regarded as intriguing oddities, are gradually being recognized as significant structural motifs. Recent experimental results show that knotting, starting from a fully extended polypeptide, has not yet been observed. Understanding the nucleation process of folding knots is thus a natural challenge for both experimental and theoretical investigation. In this study, we employ energy landscape theory and molecular dynamics to elucidate the entire folding mechanism. The full free energy landscape of a knotted protein is mapped using an all-atom structure-based protein model. Results show that, due to the topological constraint, the protein folds through a three-state mechanism that contains (i) a precise nucleation site that creates a correctly twisted native loop (first barrier) and (ii) a rate-limiting free energy barrier that is traversed by two parallel knot-forming routes. The main route corresponds to a slipknot conformation, a collapsed configuration where the C-terminal helix adopts a hairpin-like configuration while threading, and the minor route to an entropically limited plug motion, where the extended terminus is threaded as through a needle. Knot formation is a late transition state process and results show that random (nonspecific) knots are a very rare and unstable set of configurations both at and below folding temperature. Our study shows that a native-biased landscape is sufficient to fold complex topologies and presents a folding mechanism generalizable to all known knotted protein topologies: knotting via threading a native-like loop in a preordered intermediate. VL - 107 IS - 35 ER - TY - JOUR T1 - A Stevedore's protein knot. JF - PLoS Comput Biol Y1 - 2010 A1 - Bölinger, Daniel A1 - Joanna I. Sulkowska A1 - Hsu, Hsiao-Ping A1 - Mirny, Leonid A A1 - Kardar, Mehran A1 - Onuchic, José N A1 - Virnau, Peter KW - Databases, Protein KW - Hydrolases KW - Molecular Dynamics Simulation KW - Protein Conformation KW - Protein Folding AB - Protein knots, mostly regarded as intriguing oddities, are gradually being recognized as significant structural motifs. Seven distinctly knotted folds have already been identified. It is by and large unclear how these exceptional structures actually fold, and only recently, experiments and simulations have begun to shed some light on this issue. In checking the new protein structures submitted to the Protein Data Bank, we encountered the most complex and the smallest knots to date: A recently uncovered alpha-haloacid dehalogenase structure contains a knot with six crossings, a so-called Stevedore knot, in a projection onto a plane. The smallest protein knot is present in an as yet unclassified protein fragment that consists of only 92 amino acids. The topological complexity of the Stevedore knot presents a puzzle as to how it could possibly fold. To unravel this enigma, we performed folding simulations with a structure-based coarse-grained model and uncovered a possible mechanism by which the knot forms in a single loop flip. VL - 6 IS - 4 ER - TY - JOUR T1 - Theoretical study of molecular mechanism of binding TRAP220 coactivator to Retinoid X Receptor alpha, activated by 9-cis retinoic acid JF - The Journal of Steroid Biochemistry and Molecular Biology Y1 - 2010 A1 - Mateusz Kurcinski A1 - Andrzej Koliński KW - Binding Sites KW - Cell Nucleus KW - Cell Nucleus: metabolism KW - Computer Simulation KW - Crystallography KW - Humans KW - Ligands KW - Mediator Complex Subunit 1 KW - Mediator Complex Subunit 1: metabolism KW - Models KW - Molecular KW - Molecular Conformation KW - Peptides KW - Peptides: chemistry KW - Protein Binding KW - Protein Structure KW - Retinoid X Receptor alpha KW - Retinoid X Receptor alpha: metabolism KW - Tertiary KW - Theoretical KW - Tretinoin KW - Tretinoin: metabolism KW - X-Ray KW - X-Ray: methods AB -

Study on molecular mechanism of conformational reorientation of RXR-alpha ligand binding domain is presented. We employed CABS–a reduced model of protein dynamics to model folding pathways of binding 9-cis retinoic acid to apo-RXR molecule and TRAP220 peptide fragment to the holo form. Based on obtained results we also propose a sequential model of RXR activation by 9-cis retinoic acid and TRAP220 coactivator. Methodology presented here may be used for investigation of binding pathways of other NR/hormone/cofactor sets.

PB - Elsevier Ltd VL - 121 UR - http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2906686&tool=pmcentrez&rendertype=abstract ER - TY - JOUR T1 - TRACER. A new approach to comparative modeling that combines threading with free-space conformational sampling JF - Acta Biochimica Polonica Y1 - 2010 A1 - Sebastian Trojanowski A1 - Aleksandra Rutkowska A1 - Andrzej Koliński KW - Computational Biology KW - Computational Biology: methods KW - Imaging KW - Models KW - Molecular KW - Protein Conformation KW - Proteins KW - Proteins: chemistry KW - Three-Dimensional KW - Three-Dimensional: methods AB - A new approach to comparative modeling of proteins, TRACER, is described and benchmarked against classical modeling procedures. The new method unifies true three-dimensional threading with coarse-grained sampling of query protein conformational space. The initial sequence alignment of a query protein with a template is not required, although a template needs to be somehow identified. The template is used as a multi-featured fuzzy three-dimensional scaffold. The conformational search for the query protein is guided by intrinsic force field of the coarse-grained modeling engine CABS and by compatibility with the template scaffold. During Replica Exchange Monte Carlo simulations the model chain representing the query protein finds the best possible structural alignment with the template chain, that also optimizes the intra-protein interactions as approximated by the knowledge based force field of CABS. The benchmark done for a representative set of query/template pairs of various degrees of sequence similarity showed that the new method allows meaningful comparative modeling also for the region of marginal, or non-existing, sequence similarity. Thus, the new approach significantly extends the applicability of comparative modeling. VL - 57 UR - http://www.ncbi.nlm.nih.gov/pubmed/20309433 ER - TY - JOUR T1 - Untying knots in proteins. JF - Journal of the American Chemical Society Y1 - 2010 A1 - Joanna I. Sulkowska A1 - Sułkowski, Piotr A1 - Szymczak, Piotr A1 - Cieplak, Marek KW - Amino Acids KW - Protein Conformation KW - Proteins AB - A shoelace can be readily untied by pulling its ends rather than its loops. Attempting to untie a native knot in a protein can also succeed or fail depending on where one pulls. However, thermal fluctuations induced by the surrounding water affect conformations stochastically and may add to the uncertainty of the outcome. When the protein is pulled by the termini, the knot can only get tightened, and any attempt at untying results in failure. We show that, by pulling specific amino acids, one may easily retract a terminal segment of the backbone from the knotting loop and untangle the knot. At still other amino acids, the outcome of pulling can go either way. We study the dependence of the untying probability on the way the protein is grasped, the pulling speed, and the temperature. Elucidation of the mechanisms underlying this dependence is critical for a successful experimental realization of protein knot untying. VL - 132 IS - 40 ER - TY - JOUR T1 - Wpływ glikolu propylenowego na transepidermalny transport substancji czynnych JF - SOFW-Journal Polish Edition Y1 - 2010 A1 - Jacek Wabik A1 - Jacek Arct A1 - Ludwik Synoradzki VL - 2 ER - TY - JOUR T1 - Dependence of protein mechanical unfolding pathways on pulling speeds JF - The Journal of Chemical Physics Y1 - 2009 A1 - Mai Suan Li A1 - Maksim Kouza KW - biochemistry KW - free energy KW - molecular biophysics KW - Proteins PB - AIP VL - 130 UR - http://link.aip.org/link/?JCP/130/145102/1 ER - TY - JOUR T1 - Distance matrix-based approach to protein structure prediction JF - Journal of Structural and Functional Genomics Y1 - 2009 A1 - Andrzej Kloczkowski A1 - Robert L. Jernigan A1 - Zhijun Wu A1 - Guang Song A1 - Lei Yang A1 - Andrzej Koliński A1 - Piotr Pokarowski KW - Binding Sites KW - Computer Simulation KW - Databases KW - Models KW - Molecular KW - Principal Component Analysis KW - Protein KW - Protein Conformation KW - Proteins KW - Proteins: chemistry AB -

Much structural information is encoded in the internal distances; a distance matrix-based approach can be used to predict protein structure and dynamics, and for structural refinement. Our approach is based on the square distance matrix D = [r(ij)(2)] containing all square distances between residues in proteins. This distance matrix contains more information than the contact matrix C, that has elements of either 0 or 1 depending on whether the distance r (ij) is greater or less than a cutoff value r (cutoff). We have performed spectral decomposition of the distance matrices D = sigma lambda(k)V(k)V(kT), in terms of eigenvalues lambda kappa and the corresponding eigenvectors v kappa and found that it contains at most five nonzero terms. A dominant eigenvector is proportional to r (2)–the square distance of points from the center of mass, with the next three being the principal components of the system of points. By predicting r (2) from the sequence we can approximate a distance matrix of a protein with an expected RMSD value of about 7.3 A, and by combining it with the prediction of the first principal component we can improve this approximation to 4.0 A. We can also explain the role of hydrophobic interactions for the protein structure, because r is highly correlated with the hydrophobic profile of the sequence. Moreover, r is highly correlated with several sequence profiles which are useful in protein structure prediction, such as contact number, the residue-wise contact order (RWCO) or mean square fluctuations (i.e. crystallographic temperature factors). We have also shown that the next three components are related to spatial directionality of the secondary structure elements, and they may be also predicted from the sequence, improving overall structure prediction. We have also shown that the large number of available HIV-1 protease structures provides a remarkable sampling of conformations, which can be viewed as direct structural information about the dynamics. After structure matching, we apply principal component analysis (PCA) to obtain the important apparent motions for both bound and unbound structures. There are significant similarities between the first few key motions and the first few low-frequency normal modes calculated from a static representative structure with an elastic network model (ENM) that is based on the contact matrix C (related to D), strongly suggesting that the variations among the observed structures and the corresponding conformational changes are facilitated by the low-frequency, global motions intrinsic to the structure. Similarities are also found when the approach is applied to an NMR ensemble, as well as to atomic molecular dynamics (MD) trajectories. Thus, a sufficiently large number of experimental structures can directly provide important information about protein dynamics, but ENM can also provide a similar sampling of conformations. Finally, we use distance constraints from databases of known protein structures for structure refinement. We use the distributions of distances of various types in known protein structures to obtain the most probable ranges or the mean-force potentials for the distances. We then impose these constraints on structures to be refined or include the mean-force potentials directly in the energy minimization so that more plausible structural models can be built. This approach has been successfully used by us in 2006 in the CASPR structure refinement (http://predictioncenter.org/caspR).

VL - 10 UR - http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3018873&tool=pmcentrez&rendertype=abstract ER - TY - JOUR T1 - Dodging the crisis of folding proteins with knots. JF - Proceedings of the National Academy of Sciences of the United States of America Y1 - 2009 A1 - Joanna I. Sulkowska A1 - Sułkowski, Piotr A1 - Onuchic, José KW - Kinetics KW - Models, Molecular KW - Protein Folding KW - Protein Structure, Tertiary KW - Proteins AB - Proteins with nontrivial topology, containing knots and slipknots, have the ability to fold to their native states without any additional external forces invoked. A mechanism is suggested for folding of these proteins, such as YibK and YbeA, that involves an intermediate configuration with a slipknot. It elucidates the role of topological barriers and backtracking during the folding event. It also illustrates that native contacts are sufficient to guarantee folding in approximately 1-2% of the simulations, and how slipknot intermediates are needed to reduce the topological bottlenecks. As expected, simulations of proteins with similar structure but with knot removed fold much more efficiently, clearly demonstrating the origin of these topological barriers. Although these studies are based on a simple coarse-grained model, they are already able to extract some of the underlying principles governing folding in such complex topologies. VL - 106 IS - 9 ER - TY - JOUR T1 - Jamming proteins with slipknots and their free energy landscape. JF - Phys Rev Lett Y1 - 2009 A1 - Joanna I. Sulkowska A1 - Sułkowski, Piotr A1 - Onuchic, José N KW - Protein Conformation KW - Protein Folding KW - Proteins KW - Thermodynamics KW - Time Factors AB - Theoretical studies of stretching proteins with slipknots reveal a surprising growth of their unfolding times when the stretching force crosses an intermediate threshold. This behavior arises as a consequence of the existence of alternative unfolding routes that are dominant at different force ranges. The existence of an intermediate, metastable configuration where the slipknot is jammed is responsible for longer unfolding times at higher forces. Simulations are performed with a coarse-grained model with further quantification using a refined description of the geometry of the slipknots. The simulation data are used to determine the free energy landscape of the protein, which supports recent analytical predictions. VL - 103 IS - 26 ER - TY - JOUR T1 - Mechanical strength of 17,134 model proteins and cysteine slipknots. JF - PLoS Comput Biol Y1 - 2009 A1 - Sikora, Mateusz A1 - Joanna I. Sulkowska A1 - Cieplak, Marek KW - Amino Acids KW - Cysteine KW - elasticity KW - Humans KW - Models, Molecular KW - Molecular Dynamics Simulation KW - Protein Folding KW - Proteins KW - Tensile Strength AB - A new theoretical survey of proteins' resistance to constant speed stretching is performed for a set of 17,134 proteins as described by a structure-based model. The proteins selected have no gaps in their structure determination and consist of no more than 250 amino acids. Our previous studies have dealt with 7510 proteins of no more than 150 amino acids. The proteins are ranked according to the strength of the resistance. Most of the predicted top-strength proteins have not yet been studied experimentally. Architectures and folds which are likely to yield large forces are identified. New types of potent force clamps are discovered. They involve disulphide bridges and, in particular, cysteine slipknots. An effective energy parameter of the model is estimated by comparing the theoretical data on characteristic forces to the corresponding experimental values combined with an extrapolation of the theoretical data to the experimental pulling speeds. These studies provide guidance for future experiments on single molecule manipulation and should lead to selection of proteins for applications. A new class of proteins, involving cysteine slipknots, is identified as one that is expected to lead to the strongest force clamps known. This class is characterized through molecular dynamics simulations. VL - 5 IS - 10 ER - TY - JOUR T1 - Protein mechanical unfolding: Importance of non-native interactions JF - The Journal of Chemical Physics Y1 - 2009 A1 - Maksim Kouza A1 - Chin-Kun Hu A1 - Hoang Zung A1 - Mai Suan Li KW - biomechanics KW - elasticity KW - Hydrogen Bonds KW - molecular biophysics KW - molecular dynamics method KW - Proteins PB - AIP VL - 131 UR - http://link.aip.org/link/?JCP/131/215103/1 ER - TY - JOUR T1 - On the remarkable mechanostability of scaffoldins and the mechanical clamp motif. JF - Proceedings of the National Academy of Sciences of the United States of America Y1 - 2009 A1 - Valbuena, Alejandro A1 - Oroz, Javier A1 - Hervás, Rubén A1 - Vera, Andrés Manuel A1 - Rodríguez, David A1 - Menéndez, Margarita A1 - Joanna I. Sulkowska A1 - Cieplak, Marek A1 - Carrión-Vázquez, Mariano KW - Amino Acid Motifs KW - Biotechnology KW - Cellulose KW - Clostridium thermocellum KW - Computer Simulation KW - Databases, Protein KW - Kinetics KW - Microscopy, Atomic Force KW - Nanotechnology KW - Protein Conformation KW - Protein Engineering KW - Protein Folding KW - Protein Structure, Secondary KW - Proteins KW - Stress, Mechanical AB - Protein mechanostability is a fundamental biological property that can only be measured by single-molecule manipulation techniques. Such studies have unveiled a variety of highly mechanostable modules (mainly of the Ig-like, beta-sandwich type) in modular proteins subjected to mechanical stress from the cytoskeleton and the metazoan cell-cell interface. Their mechanostability is often attributed to a "mechanical clamp" of secondary structure (a patch of backbone hydrogen bonds) fastening their ends. Here we investigate the nanomechanics of scaffoldins, an important family of scaffolding proteins that assembles a variety of cellulases into the so-called cellulosome, a microbial extracellular nanomachine for cellulose adhesion and degradation. These proteins anchor the microbial cell to cellulose substrates, which makes their connecting region likely to be subjected to mechanical stress. By using single-molecule force spectroscopy based on atomic force microscopy, polyprotein engineering, and computer simulations, here we show that the cohesin I modules from the connecting region of cellulosome scaffoldins are the most robust mechanical proteins studied experimentally or predicted from the entire Protein Data Bank. The mechanostability of the cohesin modules studied correlates well with their mechanical kinetic stability but not with their thermal stability, and it is well predicted by computer simulations, even coarse-grained. This extraordinary mechanical stability is attributed to 2 mechanical clamps in tandem. Our findings provide the current upper limit of protein mechanostability and establish shear mechanical clamps as a general structural/functional motif widespread in proteins putatively subjected to mechanical stress. These data have important implications for the scaffoldin physiology and for protein design in biotechnology and nanotechnology. VL - 106 IS - 33 ER - TY - JOUR T1 - Structural changes of vitamin D receptor induced by 20-epi-1alpha,25-(OH)2D3: an insight from a computational analysis JF - The Journal of Steroid Biochemistry and Molecular Biology Y1 - 2009 A1 - Wanda Sicinska A1 - Piotr Rotkiewicz KW - Animals KW - Bone Density Conservation Agents KW - Calcitriol KW - Computer Simulation KW - Crystallography, X-Ray KW - Drug Design KW - Humans KW - Ligands KW - Molecular Structure KW - Protein Structure, Tertiary KW - Receptors, Calcitriol KW - Reproducibility of Results KW - Software KW - Transcription, Genetic AB - We employ a new computational tool CCOMP for the comparison of side chain (SC) conformations between crystal structures of homologous protein complexes. The program is applied to the vitamin D receptor (VDR) liganded with 1alpha,25-(OH)(2)D(3) (in 1DB1) or its 20-epi (in 1IE9) analog with an inverted C-20 configuration. This modification yields no detectable changes in the backbone configuration or ligand topology in the receptor binding cavity, yet it dramatically increases transcription, differentiation and antiproliferation activity of the VDR. We applied very stringent criteria during the comparison process. To eliminate errors arising from the different packing of investigated crystals and the thermal flexibility of atoms, we studied complexes belonging to the same space group, having a low R value (0.2) and a B-factor below 40 for compared residues. We find that 20-epi-1alpha,25-(OH)(2)D(3) changes side chain conformation of amino acids residing far away from direct ligand-VDR contacts. We further verify that a number of the reoriented residues were identified in mutational experiments as important for interaction with SRC-1, GRIP, TAFs co-activators and VDR-RXR heterodimerization. Thus, CCOMP analysis of protein complexes may be used for identifying amino acids that could serve as targets for genetic engineering, such as mutagenesis. VL - 113 IS - 3-5 ER - TY - JOUR T1 - Tests of the Structure-Based Models of Proteins JF - ACTA PHYSICA POLONICA A Y1 - 2009 A1 - Cieplak, Marek A1 - Joanna I. Sulkowska AB - The structure-based models of proteins are deØned through the condition that their ground state coincides with the native structure of the proteins. There are many variants of such models and they yield different properties. Optimal variants can be selected by making comparisons to experimental data on single-molecule stretching. Here, we discuss the 15 best performing variants and focus on Øne tuning the selection process by adjusting the velocity of stretching to match the experimental conditions. The very best variant is found to correspond to the 10-12 potential in the native contacts with the energies modulated by the Miyazawa{Jernigan statistical potential and variable length parameters. The second best model incorporates the Lennard{Jones potential with uniform amplitudes. We then make a detailed comparison of the two models in which theoretical surveys of stretching properties of 7510 proteins were made previously. VL - 115 IS - 2 ER - TY - JOUR T1 - AAindex: amino acid index database, progress report 2008 JF - Nucleic Acids Research Y1 - 2008 A1 - Kawashima, Shuichi A1 - Piotr Pokarowski A1 - Pokarowska, Maria A1 - Andrzej Koliński A1 - Katayama, Toshiaki A1 - Kanehisa, Minoru KW - Amino Acids KW - Amino Acids: chemistry KW - Databases KW - Internet KW - Protein KW - Proteins KW - Proteins: chemistry AB -

AAindex is a database of numerical indices representing various physicochemical and biochemical properties of amino acids and pairs of amino acids. We have added a collection of protein contact potentials to the AAindex as a new section. Accordingly AAindex consists of three sections now: AAindex1 for the amino acid index of 20 numerical values, AAindex2 for the amino acid substitution matrix and AAindex3 for the statistical protein contact potentials. All data are derived from published literature. The database can be accessed through the DBGET/LinkDB system at GenomeNet (http://www.genome.jp/dbget-bin/www\_bfind?aaindex) or downloaded by anonymous FTP (ftp://ftp.genome.jp/pub/db/community/aaindex/).

VL - 36 UR - http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2238890&tool=pmcentrez&rendertype=abstract ER - TY - JOUR T1 - Contact prediction in protein modeling: scoring, folding and refinement of coarse-grained models JF - BMC Structural Biology Y1 - 2008 A1 - Dorota Latek A1 - Andrzej Koliński KW - Algorithms KW - Caspase 6 KW - Caspase 6: chemistry KW - Caspase 6: genetics KW - Computer Simulation KW - Databases KW - Models KW - Molecular KW - Protein KW - Protein Folding KW - Proteins KW - Proteins: chemistry KW - Proteins: genetics AB -

Several different methods for contact prediction succeeded within the Sixth Critical Assessment of Techniques for Protein Structure Prediction (CASP6). The most relevant were non-local contact predictions for targets from the most difficult categories: fold recognition-analogy and new fold. Such contacts could provide valuable structural information in case a template structure cannot be found in the PDB.

VL - 8 UR - http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2527566&tool=pmcentrez&rendertype=abstract ER - TY - Generic T1 - Designing an Automatic Pipeline for Protein Structure Prediction Designing an Automatic Pipeline for Protein Structure Prediction T2 - From Computational Biophysics to Systems Biology (CBSB08) Y1 - 2008 A1 - Sebastian Kmiecik A1 - Michal Jamroz A1 - Anna Zwolinska A1 - Pawel Gniewek A1 - Andrzej Koliński A1 - Ulrich H. E. Hansmann A1 - Jan H. Meinke A1 - Sandipan Mohanty A1 - Walter Nadler A1 - Olav Zimmermann AB - Building accurate 3D structural models of proteins and protein assemblies is a challenging task. Our modeling technology is based on the CABS model, extensively tested, state-of-theart approach to protein structure prediction. The modeling process is divided into two stages: CABS fold assembly followed by the model refinement/selection procedure, using an all-atom representation and a more exact interaction scheme enabling high resolution structure prediction. Fold assembly can be done in a framework of a standard comparative modeling procedure, where spatial restraints are derived from alternative sequence alignments with a template/ templates. Preferentially in more difficult modeling cases, a new approach to comparative modeling can be used, which does not require the prior alignment. Selvita’s goal is to provide an integrated tool-kit for automated protein structure predictions. However, like blind prediction experiments show, due to high complexity of prediction tasks, fully automated approach often doesn’t guarantee the highest possible performance. Therefore, human intervention is made possible at every stage of modeling. JF - From Computational Biophysics to Systems Biology (CBSB08) VL - 40 SN - 9783981084368 ER - TY - JOUR T1 - Fast and accurate methods for predicting short-range constraints in protein models JF - Journal of Computer-Aided Molecular Design Y1 - 2008 A1 - Dominik Gront A1 - Andrzej Koliński KW - Algorithms KW - Amino Acid Sequence KW - Models KW - Molecular KW - Molecular Sequence Data KW - Predictive Value of Tests KW - Protein KW - Proteins KW - Proteins: chemistry KW - Proteins: genetics KW - Proteins: metabolism KW - Sequence Analysis KW - Software AB -

Protein modeling tools utilize many kinds of structural information that may be predicted from amino acid sequence of a target protein or obtained from experiments. Such data provide geometrical constraints in a modeling process. The main aim is to generate the best possible consensus structure. The quality of models strictly depends on the imposed conditions. In this work we present an algorithm, which predicts short-range distances between Calpha atoms as well as a set of short structural fragments that possibly share structural similarity with a query sequence. The only input of the method is a query sequence profile. The algorithm searches for short protein fragments with high sequence similarity. As a result a statistics of distances observed in the similar fragments is returned. The method can be used also as a scoring function or a short-range knowledge-based potential based on the computed statistics.

VL - 22 UR - http://www.ncbi.nlm.nih.gov/pubmed/18415023 ER - TY - JOUR T1 - Folding pathway of the b1 domain of protein G explored by multiscale modeling JF - Biophysical Journal Y1 - 2008 A1 - Sebastian Kmiecik A1 - Andrzej Koliński KW - Chemical KW - coarse-grained modeling KW - Computer Simulation KW - Models KW - Molecular KW - Molecular Dynamics Simulation KW - Nerve Tissue Proteins KW - Nerve Tissue Proteins: chemistry KW - Nerve Tissue Proteins: ultrastructure KW - Protein Conformation KW - protein dynamics KW - Protein Folding KW - Protein Structure KW - Tertiary AB - The understanding of the folding mechanisms of single-domain proteins is an essential step in the understanding of protein folding in general. Recently, we developed a mesoscopic CA-CB side-chain protein model, which was successfully applied in protein structure prediction, studies of protein thermodynamics, and modeling of protein complexes. In this research, this model is employed in a detailed characterization of the folding process of a simple globular protein, the B1 domain of IgG-binding protein G (GB1). There is a vast body of experimental facts and theoretical findings for this protein. Performing unbiased, ab initio simulations, we demonstrated that the GB1 folding proceeds via the formation of an extended folding nucleus, followed by slow structure fine-tuning. Remarkably, a subset of native interactions drives the folding from the very beginning. The emerging comprehensive picture of GB1 folding perfectly matches and extends the previous experimental and theoretical studies. PB - Elsevier VL - 94 UR - http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2186257&tool=pmcentrez&rendertype=abstract ER - TY - JOUR T1 - Inhibition of Fibril Formation of Beta-Amyloid Peptides JF - From Computational Biophysics to Systems Biology (CBSB08) Proceedings Y1 - 2008 A1 - N.S. Lam A1 - Maksim Kouza A1 - Hoang Zung A1 - Mai Suan Li VL - 40 ER - TY - JOUR T1 - New force replica exchange method and protein folding pathways probed by force-clamp technique JF - The Journal of Chemical Physics Y1 - 2008 A1 - Maksim Kouza A1 - Chin-Kun Hu A1 - Mai Suan Li KW - molecular biophysics KW - Proteins KW - Thermodynamics PB - AIP VL - 128 UR - http://link.aip.org/link/?JCP/128/045103/1 ER - TY - JOUR T1 - Predicting the complex structure and functional motions of the outer membrane transporter and signal transducer FecA JF - Biophysical journal Y1 - 2008 A1 - Taner Z. Sen A1 - Margaret Kloster A1 - Robert L. Jernigan A1 - Andrzej Koliński A1 - Janusz M. Bujnicki A1 - Andrzej Kloczkowski KW - Cell Membrane KW - Cell Membrane: chemistry KW - Cell Surface KW - Cell Surface: chemistry KW - Cell Surface: ultrastructure KW - Chemical KW - Computer Simulation KW - Escherichia coli Proteins KW - Escherichia coli Proteins: chemistry KW - Escherichia coli Proteins: ultrastructure KW - Models KW - Molecular KW - Motion KW - Protein Conformation KW - Receptors AB - Escherichia coli requires an efficient transport and signaling system to successfully sequester iron from its environment. FecA, a TonB-dependent protein, serves a critical role in this process: first, it binds and transports iron in the form of ferric citrate, and second, it initiates a signaling cascade that results in the transcription of several iron transporter genes in interaction with inner membrane proteins. The structure of the plug and barrel domains and the periplasmic N-terminal domain (NTD) are separately available. However, the linker connecting the plug and barrel and the NTD domains is highly mobile, which may prevent the determination of the FecA structure as a whole assembly. Here, we reduce the conformation space of this linker into most probable structural models using the modeling tool CABS, then apply normal-mode analysis to investigate the motions of the whole structure of FecA by using elastic network models. We relate the FecA domain motions to the outer-inner membrane communication, which initiates transcription. We observe that the global motions of FecA assign flexibility to the TonB box and the NTD, and control the exposure of the TonB box for binding to the TonB inner membrane protein, suggesting how these motions relate to FecA function. Our simulations suggest the presence of a communication between the loops on both ends of the protein, a signaling mechanism by which a signal could be transmitted by conformational transitions in response to the binding of ferric citrate. PB - Elsevier VL - 94 SN - 5152944294 UR - http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2267147&tool=pmcentrez&rendertype=abstract ER - TY - JOUR T1 - Predicting the order in which contacts are broken during single molecule protein stretching experiments. JF - Proteins Y1 - 2008 A1 - Joanna I. Sulkowska A1 - Kloczkowski, Andrzej A1 - Sen, Taner Z A1 - Cieplak, Marek A1 - Jernigan, Robert L KW - Green Fluorescent Proteins KW - Models, Chemical KW - Protein Denaturation KW - Proteins KW - Tensile Strength AB - We combine two methods to enable the prediction of the order in which contacts are broken under external stretching forces in single molecule experiments. These two methods are Gō-like models and elastic network models. The Gō-like models have shown remarkable success in representing many aspects of protein behavior, including the reproduction of experimental data obtained from atomic force microscopy. The simple elastic network models are often used successfully to predict the fluctuations of residues around their mean positions, comparing favorably with the experimentally measured crystallographic B-factors. The behavior of biomolecules under external forces has been demonstrated to depend principally on their elastic properties and the overall shape of their structure. We have studied in detail the muscle protein titin and green fluorescent protein and tested for ten other proteins. First, we stretch the proteins computationally by performing stochastic dynamics simulations with the Gō-like model. We obtain the force-displacement curves and unfolding scenarios of possible mechanical unfolding. We then use the elastic network model to calculate temperature factors (B-factors) and compare the slowest modes of motion for the stretched proteins and compare them with the predicted order of breaking contacts between residues in the Gō-like model. Our results show that a simple Gaussian network model is able to predict contacts that break in the next time stage of stretching. Additionally, we have found that the contact disruption is strictly correlated with the highest force exerted by the backbone on these residues. Our prediction of bond-breaking agrees well with the unfolding scenario obtained with the Gō-like model. We anticipate that this method will be a useful new tool for interpreting stretching experiments. VL - 71 IS - 1 ER - TY - JOUR T1 - Selection of optimal variants of Gō-like models of proteins through studies of stretching. JF - Biophys J Y1 - 2008 A1 - Joanna I. Sulkowska A1 - Cieplak, Marek KW - Analysis of Variance KW - Biomechanical Phenomena KW - Models, Molecular KW - Protein Conformation KW - Protein Folding KW - Proteins KW - Reproducibility of Results KW - Temperature KW - Thermodynamics AB - The Gō-like models of proteins are constructed based on the knowledge of the native conformation. However, there are many possible choices of a Hamiltonian for which the ground state coincides with the native state. Here, we propose to use experimental data on protein stretching to determine what choices are most adequate physically. This criterion is motivated by the fact that stretching processes usually start with the native structure, in the vicinity of which the Gō-like models should work the best. Our selection procedure is applied to 62 different versions of the Gō model and is based on 28 proteins. We consider different potentials, contact maps, local stiffness energies, and energy scales--uniform and nonuniform. In the latter case, the strength of the nonuniformity was governed either by specificity or by properties related to positioning of the side groups. Among them is the simplest variant: uniform couplings with no i, i + 2 contacts. This choice also leads to good folding properties in most cases. We elucidate relationship between the local stiffness described by a potential which involves local chirality and the one which involves dihedral and bond angles. The latter stiffness improves folding but there is little difference between them when it comes to stretching. VL - 95 IS - 7 ER - TY - JOUR T1 - Stabilizing effect of knots on proteins. JF - Proceedings of the National Academy of Sciences of the United States of America Y1 - 2008 A1 - Joanna I. Sulkowska A1 - Sulkowski, Piotr A1 - Szymczak, P A1 - Cieplak, Marek KW - Computer Simulation KW - Disulfides KW - Hot Temperature KW - Humans KW - Models, Chemical KW - Ornithine Carbamoyltransferase KW - Protein Folding KW - Protein Structure, Secondary KW - Stress, Mechanical AB - Molecular dynamics studies within a coarse-grained, structure-based model were used on two similar proteins belonging to the transcarbamylase family to probe the effects of the knot in the native structure of a protein. The first protein, N-acetylornithine transcarbamylase, contains no knot, whereas human ormithine transcarbamylase contains a trefoil knot located deep within the sequence. In addition, we also analyzed a modified transferase with the knot removed by the appropriate change of a knot-making crossing of the protein chain. The studies of thermally and mechanically induced unfolding processes suggest a larger intrinsic stability of the protein with the knot. VL - 105 IS - 50 ER - TY - JOUR T1 - Stretching to understand proteins - a survey of the protein data bank. JF - Biophys J Y1 - 2008 A1 - Joanna I. Sulkowska A1 - Cieplak, Marek KW - Computer Simulation KW - Databases, Protein KW - elasticity KW - Models, Chemical KW - Models, Molecular KW - Proteins KW - Sequence Analysis, Protein KW - Stress, Mechanical KW - Structure-Activity Relationship AB - We make a survey of resistance of 7510 proteins to mechanical stretching at constant speed as studied within a coarse-grained molecular dynamics model. We correlate the maximum force of resistance with the native structure, predict proteins which should be especially strong, and identify the nature of their force clamps. VL - 94 IS - 1 ER - TY - CHAP T1 - Template-free predictions of three-dimensional protein structures: From first principles to knowledge-based potentials T2 - Prediction of Protein Structures, Functions, and Interactions Y1 - 2008 A1 - Dominik Gront A1 - Dorota Latek A1 - Mateusz Kurcinski A1 - Andrzej Koliński A1 - Janusz M. Bujnicki JF - Prediction of Protein Structures, Functions, and Interactions PB - John Wiley & Sons CY - Chichester, UK ER - TY - JOUR T1 - Tightening of knots in proteins. JF - Phys Rev Lett Y1 - 2008 A1 - Joanna I. Sulkowska A1 - Sułkowski, Piotr A1 - Szymczak, P A1 - Cieplak, Marek KW - Algorithms KW - Diffusion KW - Models, Molecular KW - Protein Conformation KW - Solvents KW - Stochastic Processes KW - Temperature AB - We perform theoretical studies of stretching of 20 proteins with knots within a coarse-grained model. The knot's ends are found to jump to well defined sequential locations that are associated with sharp turns, whereas in homopolymers they diffuse around and eventually slide off. The waiting times of the jumps are increasingly stochastic as the temperature is raised. Knots typically do not return to their native locations when a protein is released after stretching. VL - 100 IS - 5 ER - TY - JOUR T1 - Uncharacterized DUF1574 leptospira proteins are SGNH hydrolases JF - Cell Cycle (Georgetown, Tex.) Y1 - 2008 A1 - Lukasz Knizewski A1 - Kamil Steczkiewicz A1 - Krzysztof Kuchta A1 - Lucjan Wyrwicz A1 - Dariusz Plewczynski A1 - Andrzej Koliński A1 - Leszek Rychlewski A1 - Krzysztof Ginalski KW - Amino Acid Sequence KW - Bacterial Proteins KW - Bacterial Proteins: genetics KW - Base Sequence KW - Computational Biology KW - DNA KW - Hydrolases KW - Hydrolases: genetics KW - Leptospira KW - Leptospira: enzymology KW - Models KW - Molecular KW - Molecular Sequence Data KW - Sequence Alignment KW - Sequence Analysis VL - 7 UR - http://www.ncbi.nlm.nih.gov/pubmed/18235229 ER - TY - JOUR T1 - Utility library for structural bioinformatics JF - Bioinformatics (Oxford, England) Y1 - 2008 A1 - Dominik Gront A1 - Andrzej Koliński KW - Computational Biology KW - Computational Biology: methods KW - Libraries KW - Software AB - In this Note we present a new software library for structural bioinformatics. The library contains programs, computing sequence- and profile-based alignments and a variety of structural calculations with user-friendly handling of various data formats. The software organization is very flexible. Algorithms are written in Java language and may be used by Java programs. Moreover the modules can be accessed from Jython (Python scripting language implemented in Java) scripts. Finally, the new version of BioShell delivers several utility programs that can do typical bioinformatics task from a command-line level. Availability The software is available for download free of charge from its website: http://bioshell.chem.uw.edu.pl. This website provides also numerous examples, code snippets and API documentation. VL - 24 UR - http://www.ncbi.nlm.nih.gov/pubmed/18227118 ER - TY - CHAP T1 - Wieloskalowe modelowanie białek (Multiscale protein modeling) T2 - Na pograniczu chemii i biologii (At the treshold of chemistry and biology) Y1 - 2008 A1 - Dominik Gront A1 - Dorota Latek A1 - Mateusz Kurcinski A1 - Andrzej Koliński A1 - Henryk Koroniak A1 - Jan Barciszewski JF - Na pograniczu chemii i biologii (At the treshold of chemistry and biology) PB - Wydawnictwo Naukowe UAM VL - 17 SN - 978-83-232-1847-0 ER - TY - JOUR T1 - Backbone building from quadrilaterals: a fast and accurate algorithm for protein backbone reconstruction from alpha carbon coordinates JF - Journal of Computational Chemistry Y1 - 2007 A1 - Dominik Gront A1 - Sebastian Kmiecik A1 - Andrzej Koliński KW - Algorithms KW - Carbon KW - Carbon: chemistry KW - Models KW - Molecular KW - Proteins KW - Proteins: chemistry AB - In this contribution, we present an algorithm for protein backbone reconstruction that comprises very high computational efficiency with high accuracy. Reconstruction of the main chain atomic coordinates from the alpha carbon trace is a common task in protein modeling, including de novo structure prediction, comparative modeling, and processing experimental data. The method employed in this work follows the main idea of some earlier approaches to the problem. The details and careful design of the present approach are new and lead to the algorithm that outperforms all commonly used earlier applications. BBQ (Backbone Building from Quadrilaterals) program has been extensively tested both on native structures as well as on near-native decoy models and compared with the different available existing methods. Obtained results provide a comprehensive benchmark of existing tools and evaluate their applicability to a large scale modeling using a reduced representation of protein conformational space. The BBQ package is available for downloading from our website at http://www.bioshell.pl/BBQ This webpage also provides a user manual that describes BBQ functions in detail. VL - 28 UR - http://onlinelibrary.wiley.com/doi/10.1002/jcc.20624/full http://www.ncbi.nlm.nih.gov/pubmed/17342707 ER - TY - JOUR T1 - Characterization of protein-folding pathways by reduced-space modeling JF - Proceedings of the National Academy of Sciences of the United States of America Y1 - 2007 A1 - Sebastian Kmiecik A1 - Andrzej Koliński KW - Amino Acid Sequence KW - coarse-grained modeling KW - Computational Biology KW - Computer Simulation KW - Hydrophobic and Hydrophilic Interactions KW - Models KW - Molecular KW - Molecular Dynamics Simulation KW - Monte Carlo Method KW - Protein Denaturation KW - protein dynamics KW - Protein Folding KW - Protein Structure KW - Proteins KW - Proteins: chemistry KW - Proteins: metabolism KW - Temperature KW - Tertiary AB - Ab initio simulations of the folding pathways are currently limited to very small proteins. For larger proteins, some approximations or simplifications in protein models need to be introduced. Protein folding and unfolding are among the basic processes in the cell and are very difficult to characterize in detail by experiment or simulation. Chymotrypsin inhibitor 2 (CI2) and barnase are probably the best characterized experimentally in this respect. For these model systems, initial folding stages were simulated by using CA-CB-side chain (CABS), a reduced-space protein-modeling tool. CABS employs knowledge-based potentials that proved to be very successful in protein structure prediction. With the use of isothermal Monte Carlo (MC) dynamics, initiation sites with a residual structure and weak tertiary interactions were identified. Such structures are essential for the initiation of the folding process through a sequential reduction of the protein conformational space, overcoming the Levinthal paradox in this manner. Furthermore, nucleation sites that initiate a tertiary interactions network were located. The MC simulations correspond perfectly to the results of experimental and theoretical research and bring insights into CI2 folding mechanism: unambiguous sequence of folding events was reported as well as cooperative substructures compatible with those obtained in recent molecular dynamics unfolding studies. The correspondence between the simulation and experiment shows that knowledge-based potentials are not only useful in protein structure predictions but are also capable of reproducing the folding pathways. Thus, the results of this work significantly extend the applicability range of reduced models in the theoretical study of proteins. VL - 104 UR - http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1941469&tool=pmcentrez&rendertype=abstract ER - TY - JOUR T1 - Comparative modeling without implicit sequence alignments JF - Bioinformatics (Oxford, England) Y1 - 2007 A1 - Andrzej Koliński A1 - Dominik Gront KW - Algorithms KW - Amino Acid Sequence KW - Chemical KW - Computer Simulation KW - Models KW - Molecular KW - Molecular Sequence Data KW - Protein KW - Protein Conformation KW - Protein: methods KW - Proteins KW - Proteins: chemistry KW - Proteins: ultrastructure KW - Sequence Alignment KW - Sequence Alignment: methods KW - Sequence Analysis AB -

MOTIVATION: The number of known protein sequences is about thousand times larger than the number of experimentally solved 3D structures. For more than half of the protein sequences a close or distant structural analog could be identified. The key starting point in a classical comparative modeling is to generate the best possible sequence alignment with a template or templates. With decreasing sequence similarity, the number of errors in the alignments increases and these errors are the main causes of the decreasing accuracy of the molecular models generated. Here we propose a new approach to comparative modeling, which does not require the implicit alignment - the model building phase explores geometric, evolutionary and physical properties of a template (or templates). RESULTS: The proposed method requires prior identification of a template, although the initial sequence alignment is ignored. The model is built using a very efficient reduced representation search engine CABS to find the best possible superposition of the query protein onto the template represented as a 3D multi-featured scaffold. The criteria used include: sequence similarity, predicted secondary structure consistency, local geometric features and hydrophobicity profile. For more difficult cases, the new method qualitatively outperforms existing schemes of comparative modeling. The algorithm unifies de novo modeling, 3D threading and sequence-based methods. The main idea is general and could be easily combined with other efficient modeling tools as Rosetta, UNRES and others.

VL - 23 UR - http://www.ncbi.nlm.nih.gov/pubmed/17660201 ER - TY - JOUR T1 - Computational analysis of the active sites in binary and ternary complexes of the vitamin D receptor JF - The Journal of Steroid Biochemistry and Molecular Biology Y1 - 2007 A1 - Wanda Sicinska A1 - Piotr Rotkiewicz KW - Binding Sites KW - Biomimetic Materials KW - Computer Simulation KW - Models, Molecular KW - Peptides KW - Protein Binding KW - Protein Structure, Tertiary KW - Receptors, Calcitriol KW - Solvents AB - We have developed a program CCOMP that compares overlapping fragments of two protein complexes and identifies differently oriented amino acids. CCOMP initially performs a sequence alignment of the analyzed receptors, then superimposes the corresponding aligned residues, and finally calculates the root mean square deviation (RMSD) of individual atoms, every amino acid and the entire complex. Thus, amino acids important for functional differences between both complexes can be detected. Application of CCOMP to 1alpha,25-(OH)(2)D(3)-hVDR (1DB1) [Proc. Natl. Acad. Sci. U.S.A. 98 (2001) 5491] and 1alpha,25-(OH)(2)D(3)-rVDR-peptide (1RK3) [Biochemistry 43 (2004) 4101] complexes revealed that the peptide (KNHPMLMNLLKDN) mimicking a co-activator sequence significantly changes the side chain conformation of 35 amino acids. Four of these residues (K242, I256, K260, E416) actually contact the peptide, but all of them are essential for biological activity. Only two (L309 and L400) of the 35 differently oriented amino acids contact the ligand. Interestingly, when the peptide is present (1RK3) leucine 400 shifts closer (0.7A) to the vitamin D 26-methyl group. Applying the CCOMP and DSSP programs to binary and ternary VDR complexes also resulted in establishing that seven amino acids (I238, S252, I256, L413, L415, E416, V417) exhibit significant differences in solvent accessibility and are capable of interacting with co-activators. VL - 103 IS - 3-5 ER - TY - JOUR T1 - Efficient scheme for optimization of parallel tempering Monte Carlo method JF - Journal of Physics: Condensed Matter Y1 - 2007 A1 - Dominik Gront A1 - Andrzej Koliński AB - The parallel tempering (PT) Monte Carlo sampling scheme has already been applied to studying different systems, including spin glasses and biomolecules. In this work we examine the efficiency of PT simulations and propose an iterative procedure for the optimal selection of the replicas' temperatures. The method returns a set of temperatures for a PT simulation for which the overlap of the distribution of states (referred to as an overlap ratio) measured for every pair of adjacent replicas remains constant. The computational procedure is tested for two distinct simplified molecular models of polypeptides. The method is based on the most fundamental thermodynamic properties and therefore it could be applied to virtually any system governed by the canonical ensemble. VL - 19 IS - 3 ER - TY - JOUR T1 - Hierarchical modeling of protein interactions JF - Journal of Molecular Modeling Y1 - 2007 A1 - Mateusz Kurcinski A1 - Andrzej Koliński KW - Algorithms KW - Amino Acid Sequence KW - Amino Acids KW - Amino Acids: analysis KW - Carbon KW - Carbon: chemistry KW - Computer Simulation KW - Crystallography KW - Hydrogen Bonding KW - Models KW - Molecular KW - Monte Carlo Method KW - Peptides KW - Peptides: chemistry KW - Peptides: metabolism KW - Protein Binding KW - Protein Conformation KW - Protein Structure KW - Proteins KW - Proteins: chemistry KW - Proteins: metabolism KW - Secondary KW - Stereoisomerism KW - Theoretical KW - X-Ray AB - A novel approach to hierarchical peptide-protein and protein-protein docking is described and evaluated. Modeling procedure starts from a reduced space representation of proteins and peptides. Polypeptide chains are represented by strings of alpha-carbon beads restricted to a fine-mesh cubic lattice. Side chains are represented by up to two centers of interactions, corresponding to beta-carbons and the centers of mass of the remaining portions of the side groups, respectively. Additional pseudoatoms are located in the centers of the virtual bonds connecting consecutive alpha carbons. These pseudoatoms support a model of main-chain hydrogen bonds. Docking starts from a collection of random configurations of modeled molecules. Interacting molecules are flexible; however, higher accuracy models are obtained when the conformational freedom of one (the larger one) of the assembling molecules is limited by a set of weak distance restraints extracted from the experimental (or theoretically predicted) structures. Sampling is done by means of Replica Exchange Monte Carlo method. Afterwards, the set of obtained structures is subject to a hierarchical clustering. Then, the centroids of the resulting clusters are used as scaffolds for the reconstruction of the atomic details. Finally, the all-atom models are energy minimized and scored using classical tools of molecular mechanics. The method is tested on a set of macromolecular assemblies consisting of proteins and peptides. It is demonstrated that the proposed approach to the flexible docking could be successfully applied to prediction of protein-peptide and protein-protein interactions. The obtained models are almost always qualitatively correct, although usually of relatively low (or moderate) resolution. In spite of this limitation, the proposed method opens new possibilities of computational studies of macromolecular recognition and mechanisms of assembly of macromolecular complexes. VL - 13 UR - http://www.ncbi.nlm.nih.gov/pubmed/17297609 ER - TY - JOUR T1 - Ideal amino acid exchange forms for approximating substitution matrices JF - Proteins: Structure, Function, Bioinformatics Y1 - 2007 A1 - Piotr Pokarowski A1 - Andrzej Kloczkowski A1 - Szymon Nowakowski A1 - Maria Pokarowska A1 - Robert L. Jernigan A1 - Andrzej Koliński KW - protein contact potentials KW - protein structure prediction KW - Sequence Alignment KW - substitution matrices AB - We have analyzed 29 published substitution matrices (SMs) and five statistical protein contact potentials (CPs) for comparison. We find that popular, ‘classical’ SMs obtained mainly from sequence alignments of globular proteins are mostly correlated by at least a value of 0.9. The BLOSUM62 is the central element of this group. A second group includes SMs derived from alignments of remote homologs or transmembrane proteins. These matrices correlate better with classical SMs (0.8) than among themselves (0.7). A third group consists of intermediate links between SMs and CPs - matrices and potentials that exhibit mutual correlations of at least 0.8. Next, we show that SMs can be approximated with a correlation of 0.9 by expressions c0 + xixj + yiyj + zizj, 1≤ i, j ≤ 20, where c0 is a constant and the vectors (xi), (yi), (zi) correlate highly with hydrophobicity, molecular volume and coil preferences of amino acids, respectively. The present paper is the continuation of our work (Pokarowski et al., Proteins 2005;59:49–57), where similar approximation were used to derive ideal amino acid interaction forms from CPs. Both approximations allow us to understand general trends in amino acid similarity and can help improve multiple sequence alignments using the fast Fourier transform (MAFFT), fast threading or another methods based on alignments of physicochemical profiles of protein sequences. The use of this approximation in sequence alignments instead of a classical SM yields results that differ by less than 5%. Intermediate links between SMs and CPs, new formulas for approximating these matrices, and the highly significant dependence of classical SMs on coil preferences are new findings. VL - 69 UR - http://onlinelibrary.wiley.com/doi/10.1002/prot.21509/full ER - TY - JOUR T1 - Mechanical stretching of proteins—a theoretical survey of the Protein Data Bank JF - Journal of Physics: Condensed Matter Y1 - 2007 A1 - Joanna I. Sulkowska A1 - Cieplak, Marek AB - The mechanical stretching of single proteins has been studied experimentally for about 50 proteins, yielding a variety of force patterns and peak forces. Here we perform a theoretical survey of proteins of known native structure and map out the landscape of possible dynamical behaviours under stretching at constant speed. We consider 7510 proteins comprising not more than 150 amino acids and 239 longer proteins. The model used is constructed based on the native geometry. It is solved by methods of molecular dynamics and validated by comparing the theoretical predictions to experimental results. We characterize the distribution of peak forces and investigate correlations with the system size and with the structure classification as characterized by the CATH scheme. Despite the presence of such correlations, proteins with the same CATH index may belong to different classes of dynamical behaviour. We identify proteins with the biggest forces and show that they belong to few topology classes. We determine which protein segments act as mechanical clamps and show that, in most cases, they correspond to long stretches of parallel β-strands, but other mechanisms are also possible. VL - 19 IS - 283201 ER - TY - JOUR T1 - Protein structure prediction: combining de novo modeling with sparse experimental data JF - Journal of Computational Chemistry Y1 - 2007 A1 - Dorota Latek A1 - Dariusz Ekonomiuk A1 - Andrzej Koliński KW - Algorithms KW - Computer Simulation KW - Magnetic Resonance Spectroscopy KW - Models KW - Molecular KW - Protein Folding KW - Protein Structure KW - Proteins KW - Proteins: chemistry KW - Secondary KW - Software AB - Routine structure prediction of new folds is still a challenging task for computational biology. The challenge is not only in the proper determination of overall fold but also in building models of acceptable resolution, useful for modeling the drug interactions and protein-protein complexes. In this work we propose and test a comprehensive approach to protein structure modeling supported by sparse, and relatively easy to obtain, experimental data. We focus on chemical shift-based restraints from NMR, although other sparse restraints could be easily included. In particular, we demonstrate that combining the typical NMR software with artificial intelligence-based prediction of secondary structure enhances significantly the accuracy of the restraints for molecular modeling. The computational procedure is based on the reduced representation approach implemented in the CABS modeling software, which proved to be a versatile tool for protein structure prediction during the CASP (CASP stands for critical assessment of techniques for protein structure prediction) experiments (see http://predictioncenter/CASP6/org). The method is successfully tested on a small set of representative globular proteins of different size and topology, including the two CASP6 targets, for which the required NMR data already exist. The method is implemented in a semi-automated pipeline applicable to a large scale structural annotation of genomic data. Here, we limit the computations to relatively small set. This enabled, without a loss of generality, a detailed discussion of various factors determining accuracy of the proposed approach to the protein structure prediction. VL - 28 UR - http://www.ncbi.nlm.nih.gov/pubmed/17342709 ER - TY - JOUR T1 - Refolding upon force quench and pathways of mechanical and thermal unfolding of ubiquitin JF - Biophysical Journal Y1 - 2007 A1 - Mai Suan Li A1 - Maksim Kouza A1 - Chin-Kun Hu VL - 92 UR - http://www.biomedsearch.com/nih/Refolding-upon-force-quench-pathways/17071662.html ER - TY - JOUR T1 - Steps towards flexible docking: modeling of three-dimensional structures of the nuclear receptors bound with peptide ligands mimicking co-activators' sequences JF - The Journal of Steroid Biochemistry and Molecular Biology Y1 - 2007 A1 - Mateusz Kurcinski A1 - Andrzej Koliński KW - Amino Acid Sequence KW - Crystallography KW - Cytoplasmic and Nuclear KW - Cytoplasmic and Nuclear: chemistry KW - Cytoplasmic and Nuclear: metabolism KW - Ligands KW - Models KW - Molecular KW - Molecular Mimicry KW - Peptides KW - Peptides: chemistry KW - Peptides: metabolism KW - Protein Binding KW - Protein Structure KW - Quaternary KW - Receptors KW - X-Ray AB - We developed a fully flexible docking method that uses a reduced lattice representation of protein molecules, adapted for modeling peptide-protein complexes. The CABS model (Carbon Alpha, Carbon Beta, Side Group) employed here, incorporates three pseudo-atoms per residue-Calpha, Cbeta and the center of the side group instead of full-atomic protein representation. Force field used by CABS was derived from statistical analysis of non-redundant database of protein structures. Application of our method included modeling of the complexes between various nuclear receptors (NRs) and peptide co-activators, for which three-dimensional structures are known. We tried to rebuild the native state of the complexes, starting from separated components. Accuracy of the best obtained models, calculated as coordinate root-mean-square deviation (cRMSD) between the target and the modeled structures, was under 1A, which is competitive with experimental methods, such as crystallography or NMR. Forthcoming modeling study should lead to better understanding of mechanisms of macromolecular assembly and will explain co-activators' effects on receptors activity, especially on vitamin D receptor and other nuclear receptors. VL - 103 UR - http://www.ncbi.nlm.nih.gov/pubmed/17241780 ER - TY - JOUR T1 - Towards the high-resolution protein structure prediction. Fast refinement of reduced models with all-atom force field JF - BMC Structural Biology Y1 - 2007 A1 - Sebastian Kmiecik A1 - Dominik Gront A1 - Andrzej Koliński KW - Computer Simulation KW - Models KW - Molecular KW - Protein Structure KW - protein structure prediction KW - Proteins KW - Proteins: chemistry KW - Secondary KW - Software KW - Tertiary KW - Time Factors AB - BACKGROUND: Although experimental methods for determining protein structure are providing high resolution structures, they cannot keep the pace at which amino acid sequences are resolved on the scale of entire genomes. For a considerable fraction of proteins whose structures will not be determined experimentally, computational methods can provide valuable information. The value of structural models in biological research depends critically on their quality. Development of high-accuracy computational methods that reliably generate near-experimental quality structural models is an important, unsolved problem in the protein structure modeling. RESULTS: Large sets of structural decoys have been generated using reduced conformational space protein modeling tool CABS. Subsequently, the reduced models were subject to all-atom reconstruction. Then, the resulting detailed models were energy-minimized using state-of-the-art all-atom force field, assuming fixed positions of the alpha carbons. It has been shown that a very short minimization leads to the proper ranking of the quality of the models (distance from the native structure), when the all-atom energy is used as the ranking criterion. Additionally, we performed test on medium and low accuracy decoys built via classical methods of comparative modeling. The test placed our model evaluation procedure among the state-of-the-art protein model assessment methods. CONCLUSION: These test computations show that a large scale high resolution protein structure prediction is possible, not only for small but also for large protein domains, and that it should be based on a hierarchical approach to the modeling protocol. We employed Molecular Mechanics with fixed alpha carbons to rank-order the all-atom models built on the scaffolds of the reduced models. Our tests show that a physic-based approach, usually considered computationally too demanding for large-scale applications, can be effectively used in such studies. VL - 7 SN - 1472680774 UR - http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1933428&tool=pmcentrez&rendertype=abstract ER - TY - JOUR T1 - T-Pile–a package for thermodynamic calculations for biomolecules JF - Bioinformatics (Oxford, England) Y1 - 2007 A1 - Dominik Gront A1 - Andrzej Koliński KW - Algorithms KW - Biophysics KW - Biophysics: methods KW - Computational Biology KW - Computational Biology: methods KW - Computers KW - Hot Temperature KW - Models KW - Molecular Conformation KW - Monte Carlo Method KW - Probability KW - Proteins KW - Proteins: chemistry KW - Software KW - Temperature KW - Theoretical KW - Thermodynamics AB - Molecular dynamics and Monte Carlo, usually conducted in canonical ensemble, deliver a plethora of biomolecular conformations. Proper analysis of the simulation data is a crucial part of biophysical and bioinformatics studies. Sequence alignment problem can be also formulated in terms of Boltzmann distribution. Therefore tools for efficient analysis of canonical ensemble data become extremely valuable. T-Pile package, presented here provides a user-friendly implementation of most important algorithms such as multihistogram analysis and reweighting technique. The package can be used in studies of virtually any system governed by Boltzmann distribution. AVAILABILITY: T-Pile can be downloaded from: http://biocomp.chem.uw.edu.pl/services/tpile. These pages provide a comprehensive tutorial and documentation with illustrative examples of applications. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. VL - 23 UR - http://www.ncbi.nlm.nih.gov/pubmed/17510173 ER - TY - JOUR T1 - Type II restriction endonuclease R.Eco29kI is a member of the GIY-YIG nuclease superfamily JF - BMC Structural Biology Y1 - 2007 A1 - Elena M. Ibryashkina A1 - Marina V. Zakharova A1 - Vladimir B. Baskunov A1 - Ekaterina S. Bogdanova A1 - Maxim O. Nagornykh A1 - Marat M Den'mukhamedov A1 - Bogdan S. Melnik A1 - Andrzej Koliński A1 - Dominik Gront A1 - Marcin Feder A1 - Alexander S. Solonin A1 - Janusz M. Bujnicki KW - Amino Acid Sequence KW - Binding Sites KW - Computational Biology KW - Computational Biology: methods KW - Deoxyribonucleases KW - DNA KW - DNA Cleavage KW - DNA: metabolism KW - Electrophoretic Mobility Shift Assay KW - Models KW - Molecular KW - Molecular Sequence Data KW - Mutation KW - Protein KW - Protein Conformation KW - Sequence Alignment KW - Structural Homology KW - Type II Site-Specific KW - Type II Site-Specific: chemist KW - Type II Site-Specific: metabol AB - BACKGROUND: The majority of experimentally determined crystal structures of Type II restriction endonucleases (REases) exhibit a common PD-(D/E)XK fold. Crystal structures have been also determined for single representatives of two other folds: PLD (R.BfiI) and half-pipe (R.PabI), and bioinformatics analyses supported by mutagenesis suggested that some REases belong to the HNH fold. Our previous bioinformatic analysis suggested that REase R.Eco29kI shares sequence similarities with one more unrelated nuclease superfamily, GIY-YIG, however so far no experimental data were available to support this prediction. The determination of a crystal structure of the GIY-YIG domain of homing endonuclease I-TevI provided a template for modeling of R.Eco29kI and prompted us to validate the model experimentally. RESULTS: Using protein fold-recognition methods we generated a new alignment between R.Eco29kI and I-TevI, which suggested a reassignment of one of the putative catalytic residues. A theoretical model of R.Eco29kI was constructed to illustrate its predicted three-dimensional fold and organization of the active site, comprising amino acid residues Y49, Y76, R104, H108, E142, and N154. A series of mutants was constructed to generate amino acid substitutions of selected residues (Y49A, R104A, H108F, E142A and N154L) and the mutant proteins were examined for their ability to bind the DNA containing the Eco29kI site 5'-CCGCGG-3' and to catalyze the cleavage reaction. Experimental data reveal that residues Y49, R104, E142, H108, and N154 are important for the nuclease activity of R.Eco29kI, while H108 and N154 are also important for specific DNA binding by this enzyme. CONCLUSION: Substitutions of residues Y49, R104, H108, E142 and N154 predicted by the model to be a part of the active site lead to mutant proteins with strong defects in the REase activity. These results are in very good agreement with the structural model presented in this work and with our prediction that R.Eco29kI belongs to the GIY-YIG superfamily of nucleases. Our study provides the first experimental evidence for a Type IIP REase that does not belong to the PD-(D/E)XK or HNH superfamilies of nucleases, and is instead a member of the unrelated GIY-YIG superfamily. VL - 7 SN - 1472680774 UR - http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1952068&tool=pmcentrez&rendertype=abstract ER - TY - JOUR T1 - Why do proteins divide into domains? Insights from lattice model simulations JF - Biomacromolecules Y1 - 2007 A1 - Aleksandra Rutkowska A1 - Andrzej Koliński KW - Computer Simulation KW - Models KW - Molecular KW - Polymers KW - Polymers: chemistry KW - Protein Structure KW - Proteins KW - Proteins: chemistry KW - Temperature KW - Tertiary AB -

It is known that larger globular proteins are built from domains, relatively independent structural units. A domain size seems to be limited, and a single domain consists of from few tens to a couple of hundred amino acids. Based on Monte Carlo simulations of a reduced protein model restricted to the face centered simple cubic lattice, with a minimal set of short-range and long-range interactions, we have shown that some model sequences upon the folding transition spontaneously divide into separate domains. The observed domain sizes closely correspond to the sizes of real protein domains. Short chains with a proper sequence pattern of the hydrophobic and polar residues undergo a two-state folding transition to the structurally ordered globular state, while similar longer sequences follow a multistate transition. Homopolymeric (uniformly hydrophobic) chains and random heteropolymers undergo a continuous collapse transition into a single globule, and the globular state is much less ordered. Thus, the factors responsible for the multidomain structure of proteins are sufficiently long polypeptide chain and characteristic, protein-like, sequence patterns. These findings provide some hints for the analysis of real sequences aimed at prediction of the domain structure of large proteins.

VL - 8 UR - http://www.ncbi.nlm.nih.gov/pubmed/17929971 ER - TY - CHAP T1 - Ab initio modeling T2 - Structural Genomics and High Throughput Structural Biology Y1 - 2006 A1 - Jeffrey Skolnick A1 - Yang Zhang A1 - Andrzej Koliński A1 - Michael Sundstrom A1 - Martin Norin A1 - Aled Edwards JF - Structural Genomics and High Throughput Structural Biology PB - CRC/Taylor & Francis CY - Boca Raton, FL ER - TY - JOUR T1 - BioShell–a package of tools for structural biology computations JF - Bioinformatics (Oxford, England) Y1 - 2006 A1 - Dominik Gront A1 - Andrzej Koliński KW - Chemical KW - Computational Biology KW - Computational Biology: methods KW - Computer Simulation KW - Databases KW - Models KW - Protein KW - Protein: methods KW - Proteins KW - Proteins: analysis KW - Proteins: chemistry KW - Proteins: classification KW - Sequence Alignment KW - Sequence Alignment: methods KW - Sequence Analysis KW - Software AB -

SUMMARY: BioShell is a suite of programs performing common tasks accompanying protein structure modeling. BioShell design is based on UNIX shell flexibility and should be used as its extension. Using BioShell various molecular modeling procedures can be integrated in a single pipeline. AVAILABILITY: BioShell package can be downloaded from its website http://biocomp.chem.uw.edu.pl/BioShell and these pages provide many examples and a detailed documentation for the newest version.

VL - 22 UR - http://www.ncbi.nlm.nih.gov/pubmed/16407320 ER - TY - JOUR T1 - Clustering as a supporting tool for structural drug design JF - Acta Poloniae Pharmaceutica. Drug Research Y1 - 2006 A1 - Dominik Gront A1 - Mateusz Kurcinski A1 - Andrzej Koliński KW - Cluster Analysis KW - Computer Simulation KW - Drug Design KW - Ligands KW - Models, Molecular KW - Molecular Structure KW - Protein Binding VL - 63 IS - 5 ER - TY - JOUR T1 - Correlated fluctuations of microparticles in viscoelastic solutions: quantitative measurement of material properties by microrheology in the presence of optical traps. JF - Phys Rev E Stat Nonlin Soft Matter Phys Y1 - 2006 A1 - Atakhorrami, M A1 - Joanna I. Sulkowska A1 - Addas, K M A1 - Koenderink, G H A1 - Tang, J X A1 - Levine, A J A1 - Mackintosh, F C A1 - Schmidt, C F AB - The Brownian motions of microscopic particles in viscous or viscoelastic fluids can be used to measure rheological properties. This is the basis of recently developed one- and two-particle microrheology techniques. For increased temporal and spatial resolution, some microrheology techniques employ optical traps, which introduce additional forces on the particles. We have systematically studied the effect that confinement of particles by optical traps has on their auto- and cross-correlated fluctuations. We show that trapping causes anticorrelations in the motion of two particles at low frequencies. We demonstrate how these anticorrelations depend on trap strength and the shear modulus of viscoelastic media. We present a method to account for the effects of optical traps, which permits the quantitative measurement of viscoelastic properties in one- and two-particle microrheology over an extended frequency range in a variety of viscous and viscoelastic media. VL - 73 IS - 6 Pt 1 ER - TY - JOUR T1 - Denatured proteins and early folding intermediates simulated in a reduced conformational space JF - Acta Biochimica Polonica Y1 - 2006 A1 - Sebastian Kmiecik A1 - Mateusz Kurcinski A1 - Aleksandra Rutkowska A1 - Dominik Gront A1 - Andrzej Koliński KW - Animals KW - Biophysics KW - Biophysics: methods KW - Chymotrypsin KW - Chymotrypsin: antagonists & inhibitors KW - Chymotrypsin: chemistry KW - Computer Simulation KW - Cytochromes c KW - Cytochromes c: chemistry KW - Models KW - Molecular KW - Molecular Conformation KW - Monte Carlo Method KW - Protein Conformation KW - Protein Denaturation KW - Protein Folding KW - Ribonucleases KW - Ribonucleases: chemistry KW - src Homology Domains KW - Statistical AB - Conformations of globular proteins in the denatured state were studied using a high-resolution lattice model of proteins and Monte Carlo dynamics. The model assumes a united-atom and high-coordination lattice representation of the polypeptide conformational space. The force field of the model mimics the short-range protein-like conformational stiffness, hydrophobic interactions of the side chains and the main-chain hydrogen bonds. Two types of approximations for the short-range interactions were compared: simple statistical potentials and knowledge-based protein-specific potentials derived from the sequence-structure compatibility of short fragments of protein chains. Model proteins in the denatured state are relatively compact, although the majority of the sampled conformations are globally different from the native fold. At the same time short protein fragments are mostly native-like. Thus, the denatured state of the model proteins has several features of the molten globule state observed experimentally. Statistical potentials induce native-like conformational propensities in the denatured state, especially for the fragments located in the core of folded proteins. Knowledge-based protein-specific potentials increase only slightly the level of similarity to the native conformations, in spite of their qualitatively higher specificity in the native structures. For a few cases, where fairly accurate experimental data exist, the simulation results are in semiquantitative agreement with the physical picture revealed by the experiments. This shows that the model studied in this work could be used efficiently in computational studies of protein dynamics in the denatured state, and consequently for studies of protein folding pathways, i.e. not only for the modeling of folded structures, as it was shown in previous studies. The results of the present studies also provide a new insight into the explanation of the Levinthal's paradox. VL - 53 UR - http://www.ncbi.nlm.nih.gov/pubmed/16365636 ER - TY - JOUR T1 - DFT Calculation of Nitrogen Chemical Shifts in the Active Site of Vitamin D Receptor JF - Polish Journal of Chemistry Y1 - 2006 A1 - Wanda Sicinska KW - DFT calculations of nitrogen chemical shifts KW - nuclear receptors KW - protein ligand interactions KW - vitamin D receptor AB - The complexed vitamin D receptor (VDR) is responsible for calcium homeostasis. Tryptophan is of special importance for the receptor's functions, as it appears just once in the VDR sequence and occupies the center of the ligand binding pocket. DFT calculations of nitrogen chemical shifts for Trp-NHSC moiety, presented in thiswork for liganded and free receptor, agree with NMR studies on the VDR specifically labeled with [UL] 15N2 Trp. Our calculations confirm orientation of the C(7)=C(8) vitaminDbond under the tryptophan ring. We suggest that interactions with water molecules are responsible for observed deshielding of indole Trp-nitrogen in unliganded VDR. VL - Vol. 80, no 7 ER - TY - JOUR T1 - Effect of Finite Size on Cooperativity and Rates of Protein Folding†JF - The Journal of Physical Chemistry A Y1 - 2006 A1 - Maksim Kouza A1 - Mai Suan Li A1 - Edward P. O'Brien A1 - Chin-Kun Hu A1 - D. Thirumalai VL - 110 UR - http://pubs.acs.org/doi/abs/10.1021/jp053770b ER - TY - Generic T1 - High throughput method for protein structure prediction T2 - NIC Workshop 2006: From Computational Biophysics to System Biology Y1 - 2006 A1 - Dominik Gront A1 - Sebastian Kmiecik A1 - Andrzej Koliński A1 - Jan H. Meinke A1 - Michael T. Zimmermann A1 - Sandipan Mohanty A1 - Ulrich H. E. Hansmann AB - Recently several successful methods for protein structure prediction have been proposed. Next step towards modeling on a genomic scale is to combine existing tools into a single automated
protocol. Such methods are crucial to fill the gap between the number of currently known protein sequences and structures. Here we utilize a lattice based coarse-grained modeling algorithm
together with several accompanying tools to build a generalized pipeline for protein structure prediction. Our strategy was successfully applied during the CASP6 experiment. JF - NIC Workshop 2006: From Computational Biophysics to System Biology T3 - Publication Series of the John von Neumann Institute for Computing (NIC) PB - John von Neumann Institute for Computing CY - Julich VL - 34 ER - TY - Generic T1 - Modeling protein structure, dynamics and thermodynamics with reduced representation of conformational space T2 - NIC Workshop 2006: From Computational Biophysics to System Biology Y1 - 2006 A1 - Andrzej Koliński A1 - Dominik Gront A1 - Sebastian Kmiecik A1 - Mateusz Kurcinski A1 - Dorota Latek A1 - Jan H. Meinke A1 - Michael T. Zimmermann A1 - Sandipan Mohanty A1 - Ulrich H. E. Hansmann AB - In this contribution we describe a successful approach to protein modeling which is based on reduced representation of protein conformational space, all-atom-refinement, evaluation and selection of the best molecular models. During the sixth CASP (Critical Assessment of protein Structure Prediction) community-wide experiment our methodology (referred further as CABS) proven to be one of the best performing methods for protein structure prediction, applied both for comparative modeling and to de novo folding. The newest applications of the CABS modeling technology include: study of protein folding thermodynamic, dynamics in the denatured state and folding pathways, structure prediction based on sparse and inaccurate experimental data and prediction of protein-protein interactions or flexible ligand docking. The CABS reduced model could be easily integrated with the all-atom approaches providing solid starting point for reliable multiscale simulations of large biomolecular systems. JF - NIC Workshop 2006: From Computational Biophysics to System Biology T3 - Publication Series of the John von Neumann Institute for Computing (NIC) PB - John von Neumann Institute for Computing CY - Julich VL - 34 ER - TY - CHAP T1 - Theoretical models and simulations of polymer chains T2 - Physical Properties of Polymers Handbook Y1 - 2006 A1 - Andrzej Kloczkowski A1 - Andrzej Koliński A1 - James E. Mark KW - Polymers JF - Physical Properties of Polymers Handbook PB - Springer CY - New York ER - TY - JOUR T1 - Three dimensional model of severe acute respiratory syndrome coronavirus helicase ATPase catalytic domain and molecular design of severe acute respiratory syndrome coronavirus helicase inhibitors JF - Journal of Computer-Aided Molecular Design Y1 - 2006 A1 - Marcin Hoffmann A1 - Krystian Eitner A1 - Marcin von Grotthuss A1 - Leszek Rychlewski A1 - Ewa Banachowicz A1 - Tomasz Grabarkiewicz A1 - Tomasz Szkoda A1 - Andrzej Koliński KW - Amino Acid Sequence KW - Catalytic Domain KW - Conserved Sequence KW - DNA Helicases KW - DNA Helicases: antagonists & inhibitors KW - DNA Helicases: chemistry KW - Drug Design KW - Enzyme Inhibitors KW - Enzyme Inhibitors: pharmacology KW - Models KW - Molecular KW - Molecular Sequence Data KW - Protein KW - SARS Virus KW - SARS Virus: enzymology KW - Sequence Alignment KW - Structural Homology KW - Thermodynamics AB - The modeling of the severe acute respiratory syndrome coronavirus helicase ATPase catalytic domain was performed using the protein structure prediction Meta Server and the 3D Jury method for model selection, which resulted in the identification of 1JPR, 1UAA and 1W36 PDB structures as suitable templates for creating a full atom 3D model. This model was further utilized to design small molecules that are expected to block an ATPase catalytic pocket thus inhibit the enzymatic activity. Binding sites for various functional groups were identified in a series of molecular dynamics calculation. Their positions in the catalytic pocket were used as constraints in the Cambridge structural database search for molecules having the pharmacophores that interacted most strongly with the enzyme in a desired position. The subsequent MD simulations followed by calculations of binding energies of the designed molecules were compared to ATP identifying the most successful candidates, for likely inhibitors - molecules possessing two phosphonic acid moieties at distal ends of the molecule. VL - 20 UR - http://www.ncbi.nlm.nih.gov/pubmed/16972168 ER - TY - JOUR T1 - DNA vaccine expressing the mimotope of GD2 ganglioside induces protective GD2 cross-reactive antibody responses JF - Cancer Research Y1 - 2005 A1 - Elizabeth Bolesta A1 - Aleksandra Kowalczyk A1 - Andrzej Wierzbicki A1 - Piotr Rotkiewicz A1 - Barbara Bambach A1 - Chun-Yen Tsao A1 - Irena Horwacik A1 - Andrzej Koliński A1 - Hanna Rokita A1 - Martin Brecher A1 - Xinhui Wang A1 - Soldano Ferrone A1 - Danuta Kozbor KW - Active KW - Active: methods KW - Amino Acid Sequence KW - Animals KW - Antibodies KW - Antibody KW - Binding Sites KW - Cancer Vaccines KW - Cancer Vaccines: genetics KW - Cancer Vaccines: immunology KW - Cancer Vaccines: pharmacology KW - Cross Reactions KW - DNA KW - DNA: genetics KW - DNA: immunology KW - DNA: pharmacology KW - Female KW - Gangliosides KW - Gangliosides: genetics KW - Gangliosides: immunology KW - Humans KW - Immunoglobulin G KW - Immunoglobulin G: biosynthesis KW - Immunoglobulin G: immunology KW - Immunotherapy KW - Inbred BALB C KW - Melanoma KW - Melanoma: immunology KW - Melanoma: therapy KW - Mice KW - Molecular Sequence Data KW - Monoclonal KW - Monoclonal: genetics KW - Monoclonal: immunology KW - Neuroblastoma KW - Neuroblastoma: immunology KW - Neuroblastoma: therapy KW - Peptide Library KW - Peptides KW - Peptides: genetics KW - Peptides: immunology KW - SCID KW - Vaccines KW - Xenograft Model Antitumor Assays AB - The GD2 ganglioside expressed on neuroectodermally derived tumors, including neuroblastoma and melanoma, is weakly immunogenic in tumor-bearing patients and induces predominantly immunoglobulin (Ig)-M antibody responses in the immunized host. Here, we investigated whether interconversion of GD2 into a peptide mimetic form would induce GD2 cross-reactive IgG antibody responses in mice. Screening of the X(15) phage display peptide library with the anti-GD2 monoclonal antibody (mAb) 14G2a led to isolation of mimetic peptide 47, which inhibited the binding of 14G2a antibody to GD2-positive tumor cells. The peptide was also recognized by GD2-specific serum antibodies from a patient with neuroblastoma, suggesting that it bears an internal image of GD2 ganglioside expressed on the tumor cells. The molecular basis for antigenicity of the GD2 mimetic peptide, established by molecular modeling and mutagenesis studies, led to the generation of a 47-LDA mutant with an increased mimicry to GD2. Immunization of mice with peptide 47-LDA-encoded plasmid DNA elicited GD2 cross-reactive IgG antibody responses, which were increased on subsequent boost with GD2 ganglioside. The vaccine-induced antibodies recognized GD2-positive tumor cells, mediated complement-dependent cytotoxicity, and exhibited protection against s.c. human GD2-positive melanoma growth in the severe combined immunodeficient mouse xenograft model. The results from our studies provide insights into approaches for boosting GD2 cross-reactive IgG antibody responses by minigene vaccination with a protective epitope of GD2 ganglioside. VL - 65 SN - 7168458906 UR - http://www.ncbi.nlm.nih.gov/pubmed/15833876 ER - TY - JOUR T1 - Exploring protein energy landscapes with hierarchical clustering JF - International Journal of Quantum Chemistry Y1 - 2005 A1 - Dominik Gront A1 - Ulrich H. E. Hansmann A1 - Andrzej Koliński KW - energy landscape KW - hierarchical clustering KW - homology KW - modeling KW - monte carlo sampling KW - Protein Folding KW - protein lattice model AB - In this work we present a new method for investigating local energy minima on a protein energy landscape. The CABS (CAlpha, CBeta and the center of mass of the Side chain) method was employed for generating protein models, but any other method could be used instead. Cα traces from an ensemble of models are hierarchical clustered with the HCPM (Hierarchical Clustering of Protein Models) method. The efficiency of this method for sampling and analyzing energy landscapes is shown. VL - 105 UR - http://onlinelibrary.wiley.com/doi/10.1002/qua.20741/full ER - TY - JOUR T1 - Folding of the protein domain hbSBD JF - Biophys J Y1 - 2005 A1 - Maksim Kouza A1 - C. Chang A1 - S. Hayryan A1 - T. Yu A1 - Mai Suan Li A1 - T. Huang A1 - C. Hu AB - The folding of the alpha-helix domain hbSBD of the mammalian mitochondrial branched-chain alpha-ketoacid dehydrogenase complex is studied by the circular dichroism technique in absence of urea. Thermal denaturation is used to evaluate various thermodynamic parameters defining the equilibrium unfolding, which is well described by the two-state model with the folding temperature T(F) = 317.8 +/- 1.95 K and the enthalpy change DeltaH(G) = 19.67 +/- 2.67 kcal/mol. The folding is also studied numerically using the off-lattice coarse-grained Go model and the Langevin dynamics. The obtained results, including the population of the native basin, the free-energy landscape as a function of the number of native contacts, and the folding kinetics, also suggest that the hbSBD domain is a two-state folder. These results are consistent with the biological function of hbSBD in branched-chain alpha-ketoacid dehydrogenase. VL - 89 ER - TY - JOUR T1 - Generalized protein structure prediction based on combination of fold-recognition with de novo folding and evaluation of models JF - Proteins Y1 - 2005 A1 - Andrzej Koliński A1 - Janusz M. Bujnicki KW - Algorithms KW - Computational Biology KW - Computational Biology: methods KW - Computer Simulation KW - Computers KW - Data Interpretation KW - Databases KW - Dimerization KW - Models KW - Molecular KW - Monte Carlo Method KW - Protein KW - Protein Conformation KW - Protein Folding KW - Protein Structure KW - Proteomics KW - Proteomics: methods KW - Reproducibility of Results KW - Secondary KW - Sequence Alignment KW - Software KW - Statistical KW - Tertiary AB - To predict the tertiary structure of full-length sequences of all targets in CASP6, regardless of their potential category (from easy comparative modeling to fold recognition to apparent new folds) we used a novel combination of two very different approaches developed independently in our laboratories, which ranked quite well in different categories in CASP5. First, the GeneSilico metaserver was used to identify domains, predict secondary structure, and generate fold recognition (FR) alignments, which were converted to full-atom models using the "FRankenstein's Monster" approach for comparative modeling (CM) by recombination of protein fragments. Additional models generated "de novo" by fully automated servers were obtained from the CASP website. All these models were evaluated by VERIFY3D, and residues with scores better than 0.2 were used as a source of spatial restraints. Second, a new implementation of the lattice-based protein modeling tool CABS was used to carry out folding guided by the above-mentioned restraints with the Replica Exchange Monte Carlo sampling technique. Decoys generated in the course of simulation were subject to the average linkage hierarchical clustering. For a representative decoy from each cluster, a full-atom model was rebuilt. Finally, five models were selected for submission based on combination of various criteria, including the size, density, and average energy of the corresponding cluster, and the visual evaluation of the full-atom structures and their relationship to the original templates. The combination of FRankenstein and CABS was one of the best-performing algorithms over all categories in CASP6 (it is important to note that our human intervention was very limited, and all steps in our method can be easily automated). We were able to generate a number of very good models, especially in the Comparative Modeling and New Folds categories. Frequently, the best models were closer to the native structure than any of the templates used. The main problem we encountered was in the ranking of the final models (the only step of significant human intervention), due to the insufficient computational power, which precluded the possibility of full-atom refinement and energy-based evaluation. VL - 61 Suppl. 7 UR - http://www.ncbi.nlm.nih.gov/pubmed/16187348 ER - TY - JOUR T1 - HCPM–program for hierarchical clustering of protein models JF - Bioinformatics Y1 - 2005 A1 - Dominik Gront A1 - Andrzej Koliński KW - Algorithms KW - Chemical KW - Cluster Analysis KW - Computer Simulation KW - Internet KW - Models KW - Molecular KW - Protein KW - Protein: methods KW - Proteins KW - Proteins: analysis KW - Proteins: chemistry KW - Sequence Alignment KW - Sequence Alignment: methods KW - Sequence Analysis KW - Software KW - User-Computer Interface AB - HCPM is a tool for clustering protein structures from comparative modeling, ab initio structure prediction, etc. A hierarchical clustering algorithm is designed and tested, and a heuristic is provided for an optimal cluster selection. The method has been successfully tested during the CASP6 experiment. VL - 21 UR - http://www.ncbi.nlm.nih.gov/pubmed/15840705 ER - TY - JOUR T1 - Inferring ideal amino acid interaction forms from statistical protein contact potentials JF - Proteins Y1 - 2005 A1 - Piotr Pokarowski A1 - Andrzej Kloczkowski A1 - Robert L. Jernigan A1 - Neha S. Kothari A1 - Maria Pokarowska A1 - Andrzej Koliński KW - Amino Acids KW - Amino Acids: chemistry KW - Binding Sites KW - Models KW - Molecular KW - Proteins KW - Proteins: chemistry KW - Statistical KW - Theoretical AB - We have analyzed 29 different published matrices of protein pairwise contact potentials (CPs) between amino acids derived from different sets of proteins, either crystallographic structures taken from the Protein Data Bank (PDB) or computer-generated decoys. Each of the CPs is similar to 1 of the 2 matrices derived in the work of Miyazawa and Jernigan (Proteins 1999;34:49-68). The CP matrices of the first class can be approximated with a correlation of order 0.9 by the formula e(ij) = h(i) + h(j), 1 MOTIVATION: Knowledge-based potentials are valuable tools for protein structure modeling and evaluation of the quality of the structure prediction obtained by a variety of methods. Potentials of such type could be significantly enhanced by a proper exploitation of the evolutionary information encoded in related protein sequences. The new potentials could be valuable components of threading algorithms, ab-initio protein structure prediction, comparative modeling and structure modeling based on fragmentary experimental data. RESULTS: A new potential for scoring local protein geometry is designed and evaluated. The approach is based on the similarity of short protein fragments measured by an alignment of their sequence profiles. Sequence specificity of the resulting energy function has been compared with the specificity of simpler potentials using gapless threading and the ability to predict specific geometry of protein fragments. Significant improvement in threading sensitivity and in the ability to generate sequence-specific protein-like conformations has been achieved.

VL - 21 UR - http://www.ncbi.nlm.nih.gov/pubmed/15509604 ER - TY - JOUR T1 - NMR assignments of tryptophan residue in apo and holo LBD-rVDR JF - Proteins Y1 - 2005 A1 - Wanda Sicinska A1 - William M. Westler A1 - Hector F. DeLuca KW - Animals KW - Apoproteins KW - Binding Sites KW - Ligands KW - Magnetic Resonance Spectroscopy KW - Rats KW - Receptors, Calcitriol KW - Tryptophan KW - Vitamin D AB - Binding sites in the full-length, ligand-binding domain of rat vitamin D receptor (LBD-rVDR) for an active hormone derived from vitamin D (1alpha,25-dihydroxyvitamin D(3)) and three of its C-2 substituted analogs were compared by nuclear magnetic resonance (NMR) spectroscopy. Specific residue labeled with [UL]-(15)N(2) Trp allowed assignment of the side-chain H(epsilon1) and N(epsilon1) resonances of the single tryptophan residue at position 282 in LBD-rVDR. Comparison of (1)H[(15)N] Heteronuclear Single Quantum Correlation (HSQC) spectra of apo and holo LBD-rVDR revealed that the position of the Trp282 H(epsilon1) and N(epsilon1) signals are sensitive to the presence of the ligand in the receptor cavity. Binding of the ligands to LBD-rVDR results in a shift of both Trp H(epsilon1) and N(epsilon1) resonances to lower frequencies. The results indicate that the interaction between the ligands and Trp282 is not responsible for differences in calcemic activity observed in vitamin D analogs. VL - 61 IS - 3 ER - TY - JOUR T1 - Protein Folding with a Reduced Model and Inaccurate Short-Range Restraints JF - Macromolecular Theory and Simulations Y1 - 2005 A1 - Dorota Plewczynska A1 - Andrzej Koliński KW - dihedral angles KW - Monte Carlo simulation KW - Proteins KW - reduced models KW - structure prediction AB - Summary: A reduced high-coordination lattice protein model and the Replica Exchange Monte Carlo sampling were employed in de novo folding simulations of a set of representative small proteins. Three distinct situations were analyzed. In the first series of simulations, the folding was controlled purely by the generic force field of the model. In the second, a bias was introduced towards the theoretically predicted secondary structure. Finally, we superimposed soft restraints towards the native-like local conformation of the backbone. The short-range restraints used in these simulations are based on approximate values of ϕ and ψ dihedral angles, which may simulate restraints derived from inaccurate experimental measurements. Incorporating such data into the reduced model required developing a procedure, which transforms the ϕ and ψ coordinates into coordinates of the protein alpha carbon trace. It has been shown that such limited data are sufficient for de novo determination of three-dimensional structures of small and topologically not too complex proteins. VL - 14 UR - http://dx.doi.org/10.1002/mats.200500020 ER - TY - JOUR T1 - Protein modeling with reduced representation: statistical potentials and protein folding mechanism JF - Acta Biochimica Polonica Y1 - 2005 A1 - Dariusz Ekonomiuk A1 - Marcin Kielbasinski A1 - Andrzej Koliński KW - Biophysical Phenomena KW - Biophysics KW - Computer Simulation KW - Models KW - Molecular KW - Monte Carlo Method KW - Protein Conformation KW - Protein Folding KW - Proteins KW - Proteins: chemistry KW - Proteins: metabolism AB - A high resolution reduced model of proteins is used in Monte Carlo dynamics studies of the folding mechanism of a small globular protein, the B1 immunoglobulin-binding domain of streptococcal protein G. It is shown that in order to reproduce the physics of the folding transition, the united atom based model requires a set of knowledge-based potentials mimicking the short-range conformational propensities and protein-like chain stiffness, a model of directional and cooperative hydrogen bonds, and properly designed knowledge-based potentials of the long-range interactions between the side groups. The folding of the model protein is cooperative and very fast. In a single trajectory, a number of folding/unfolding cycles were observed. Typically, the folding process is initiated by assembly of a native-like structure of the C-terminal hairpin. In the next stage the rest of the four-ribbon beta-sheet folds. The slowest step of this pathway is the assembly of the central helix on the scaffold of the beta-sheet. VL - 52 UR - http://www.ncbi.nlm.nih.gov/pubmed/15933762 ER - TY - JOUR T1 - Protein structure prediction by tempering spatial constraints JF - Journal of Computer-Aided Molecular Design Y1 - 2005 A1 - Dominik Gront A1 - Andrzej Koliński A1 - Ulrich H. E. Hansmann KW - Algorithms KW - Computer Simulation KW - Monte Carlo Method KW - Protein Conformation KW - Temperature AB - The probability to predict correctly a protein structure can be enhanced through introduction of spatial constraints - either from NMR experiments or from homologous structures. However, the additional constraints lead often to new local energy minima and worse sampling efficiency in simulations. In this work, we present a new parallel tempering variant that alleviates the energy barriers resulting from spatial constraints and therefore yields to an enhanced sampling in structure prediction simulations. VL - 19 SN - 1082200590160 UR - http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1473033&tool=pmcentrez&rendertype=abstract ER - TY - JOUR T1 - Theoretical model of prion propagation: a misfolded protein induces misfolding JF - Proceedings of the National Academy of Sciences of the United States of America Y1 - 2005 A1 - Edyta Małolepsza A1 - Michal Boniecki A1 - Andrzej Koliński A1 - Lucjan Piela KW - Amino Acid Sequence KW - Amino Acids KW - Amino Acids: metabolism KW - Computer Simulation KW - Models KW - Molecular KW - Monte Carlo Method KW - Prions KW - Prions: metabolism KW - Protein Conformation KW - Protein Folding KW - Theoretical AB - There is a hypothesis that dangerous diseases such as bovine spongiform encephalopathy, Creutzfeldt-Jakob, Alzheimer's, fatal familial insomnia, and several others are induced by propagation of wrong or misfolded conformations of some vital proteins. If for some reason the misfolded conformations were acquired by many such protein molecules it might lead to a "conformational" disease of the organism. Here, a theoretical model of the molecular mechanism of such a conformational disease is proposed, in which a metastable (or misfolded) form of a protein induces a similar misfolding of another protein molecule (conformational autocatalysis). First, a number of amino acid sequences composed of 32 aa have been designed that fold rapidly into a well defined native-like alpha-helical conformation. From a large number of such sequences a subset of 14 had a specific feature of their energy landscape, a well defined local energy minimum (higher than the global minimum for the alpha-helical fold) corresponding to beta-type structure. Only one of these 14 sequences exhibited a strong autocatalytic tendency to form a beta-sheet dimer capable of further propagation of protofibril-like structure. Simulations were done by using a reduced, although of high resolution, protein model and the replica exchange Monte Carlo sampling procedure. VL - 102 SN - 0409389102 UR - http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1142357&tool=pmcentrez&rendertype=abstract ER - TY - JOUR T1 - Thermal unfolding of proteins. JF - J Chem Phys Y1 - 2005 A1 - Cieplak, Marek A1 - Joanna I. Sulkowska KW - Chemistry, Physical KW - Computer Simulation KW - Connectin KW - Kinetics KW - Models, Molecular KW - Molecular Conformation KW - Muscle Proteins KW - Protein Conformation KW - Protein Denaturation KW - Protein Folding KW - Protein Kinases KW - Protein Structure, Secondary KW - Proteins KW - Temperature KW - Time Factors AB - Thermal unfolding of proteins is compared to folding and mechanical stretching in a simple topology-based dynamical model. We define the unfolding time and demonstrate its low-temperature divergence. Below a characteristic temperature, contacts break at separate time scales and unfolding proceeds approximately in a way reverse to folding. Features in these scenarios agree with experiments and atomic simulations on titin. VL - 123 IS - 19 ER - TY - JOUR T1 - 2-Methylene analogs of 1alpha-hydroxy-19-norvitamin D3: synthesis, biological activities and docking to the ligand binding domain of the rat vitamin D receptor JF - The Journal of Steroid Biochemistry and Molecular Biology Y1 - 2004 A1 - Pawel Grzywacz A1 - Lori A. Plum A1 - Wanda Sicinska A1 - Rafal R. Sicinski A1 - Jean M. Prahl A1 - Hector F. DeLuca KW - Animals KW - Binding Sites KW - Calcitriol KW - Female KW - HL-60 Cells KW - Humans KW - Hydrocarbons KW - Ligands KW - Methane KW - Mice KW - Models, Molecular KW - Rats KW - Receptors, Calcitriol AB - In continuing efforts towards the synthesis of biologically active vitamin D compounds of potential therapeutic value, new 2-methylene-1alpha-hydroxy-19-norvitamin D(3) analogs 3 and 4 with modified alkyl side chains have been synthesized. The key synthetic step involved Lythgoe-type Wittig-Horner coupling of Windaus-Grundmann type ketones 9, possessing different 17beta-alkyl substituents, with the phosphine oxide 10 prepared from (-)-quinic acid. The prepared vitamins 3 and 4 were ca. eight times less potent than 1alpha,25-dihydroxyvitamin D(3) (1alpha,25-(OH)(2)D(3)) (1) in binding to the rat intestinal vitamin D receptor (VDR). In comparison with the hormone 1 they exhibited slightly lower cellular HL-60 differentiation activity. When tested in vivo; the analog 3 was characterized by very high bone calcium mobilizing potency and intestinal calcium transport activity. Unexpectedly, the 25-methyl compound 4 showed marked calcemic activity in both assays. Computational docking of the vitamin 3 into the binding pocket of the rat vitamin D receptor is also reported. VL - 89-90 IS - 1-5 ER - TY - JOUR T1 - Model of three-dimensional structure of VDR bound with Vitamin D3 analogs substituted at carbon-2 JF - The Journal of Steroid Biochemistry and Molecular Biology Y1 - 2004 A1 - Wanda Sicinska A1 - Piotr Rotkiewicz A1 - Hector F. DeLuca KW - Animals KW - Calcium KW - Carbon KW - Cholecalciferol KW - Ligands KW - Models, Molecular KW - Molecular Conformation KW - Rats KW - Receptors, Calcitriol AB - All Vitamin D analogs possessing the A ring modified at C-2 and showing calcemic activities nest themselves in the VDR binding pocket, oriented towards Tyr 143. Such topology resembles the position of the Vitamin D hormone in hVDRmt [Proc. Natl. Acad. Sci. U.S.A. 98 (2001) 5491]. Conversely, inactive 2beta-methyl-19-nor-analogs anchor the receptor cavity in a distinguishably different manner, namely by their side chain. Moreover, these inactive vitamins have a different conformation around C(6)-C(7) bond. Topology of modeled complexes suggests that a Vitamin D analog will be biologically active if its intercyclic 5,7-diene moiety assumes parallel position to tryptophan aromatic rings; such orientation allows for creating pi-pi interactions. The broad comparison of calcemic activities of the analogs, and their interactions with VDR, revealed that specific hydrophobic contacts are involved in bone calcium mobilization (BCM). These contacts occur between 21-methyl group and a few amino acids (V296, L305 and L309), conserved in the nuclear receptor superfamily. In the inactive 2beta-methyl-19-nor analogs such contacts do not exist. We speculate that two hydrophobic receptor patches, being in close contact with ligand methyl groups, might influence interaction with co-modulators involved in calcium homeostasis. VL - 89-90 IS - 1-5 ER - TY - JOUR T1 - Protein modeling and structure prediction with a reduced representation JF - Acta Biochimica Polonica Y1 - 2004 A1 - Andrzej Koliński KW - Amino Acid Sequence KW - Animals KW - Carbon KW - Carbon: chemistry KW - Crystallography KW - Databases as Topic KW - Humans KW - Hydrogen Bonding KW - Mathematics KW - Models KW - Molecular KW - Molecular Sequence Data KW - Protein Conformation KW - Protein Structure KW - Proteins KW - Proteins: chemistry KW - Proteomics KW - Proteomics: methods KW - Tertiary KW - Theoretical KW - X-Ray AB -

Protein modeling could be done on various levels of structural details, from simplified lattice or continuous representations, through high resolution reduced models, employing the united atom representation, to all-atom models of the molecular mechanics. Here I describe a new high resolution reduced model, its force field and applications in the structural proteomics. The model uses a lattice representation with 800 possible orientations of the virtual alpha carbon-alpha carbon bonds. The sampling scheme of the conformational space employs the Replica Exchange Monte Carlo method. Knowledge-based potentials of the force field include: generic protein-like conformational biases, statistical potentials for the short-range conformational propensities, a model of the main chain hydrogen bonds and context-dependent statistical potentials describing the side group interactions. The model is more accurate than the previously designed lattice models and in many applications it is complementary and competitive in respect to the all-atom techniques. The test applications include: the ab initio structure prediction, multitemplate comparative modeling and structure prediction based on sparse experimental data. Especially, the new approach to comparative modeling could be a valuable tool of the structural proteomics. It is shown that the new approach goes beyond the range of applicability of the traditional methods of the protein comparative modeling.

VL - 51 UR - http://www.ncbi.nlm.nih.gov/pubmed/15218533 ER - TY - JOUR T1 - Reduced models of proteins and their applications JF - Polymer Y1 - 2004 A1 - Andrzej Koliński A1 - Jeffrey Skolnick KW - Lattice proteins KW - Protein Folding KW - Reduced protein models AB - Reduced computer modeling of proteins now has a history of about 30 years. In spite of the enormous increase in computing abilities, reduced models are still very important tools for theoretical studies of protein structure, dynamics and thermodynamics. Very simple, highly idealized lattice (and recently also off-lattice) models could be studied in great detail, providing valuable insight into the most general factors governing structure stability, folding kinetics and interactions responsible for characteristic two-state behavior near the folding temperature. More complex models now enable modeling of real proteins on the level of low to moderate resolution, allowing us to address more detailed questions. Ab initio protein structure predictions, still being far from a routine task, have become feasible. When supported by evolutionary information from multiple sequence alignments and potential local and/or global structural similarity to known structures, reduced modeling opens up new areas of comparative modeling, thereby complementing contemporary structural genomics. VL - 45 UR - http://www.sciencedirect.com/science/article/pii/S0032386103009923 http://linkinghub.elsevier.com/retrieve/pii/S0032386103009923 ER - TY - JOUR T1 - A minimal physically realistic protein-like lattice model: designing an energy landscape that ensures all-or-none folding to a unique native state JF - Biophysical Journal Y1 - 2003 A1 - Piotr Pokarowski A1 - Andrzej Koliński A1 - Jeffrey Skolnick KW - Amino Acid Motifs KW - Computer Simulation KW - Crystallography KW - Crystallography: methods KW - Energy Transfer KW - Entropy KW - Mechanical KW - Models KW - Molecular KW - Monte Carlo Method KW - Peptides KW - Peptides: chemistry KW - Protein Conformation KW - Protein Folding KW - Protein Structure KW - Proteins KW - Proteins: chemistry KW - Static Electricity KW - Stress KW - Tertiary AB - A simple protein model restricted to the face-centered cubic lattice has been studied. The model interaction scheme includes attractive interactions between hydrophobic (H) residues, repulsive interactions between hydrophobic and polar (P) residues, and orientation-dependent P-P interactions. Additionally, there is a potential that favors extended beta-type conformations. A sequence has been designed that adopts a native structure, consisting of an antiparallel, six-member Greek-key beta-barrel with protein-like structural degeneracy. It has been shown that the proposed model is a minimal one, i.e., all the above listed types of interactions are necessary for cooperative (all-or-none) type folding to the native state. Simulations were performed via the Replica Exchange Monte Carlo method and the numerical data analyzed via a multihistogram method. VL - 84 UR - http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1302725&tool=pmcentrez&rendertype=abstract ER - TY - JOUR T1 - Protein fragment reconstruction using various modeling techniques JF - Journal of Computer-Aided Molecular Design Y1 - 2003 A1 - Michal Boniecki A1 - Piotr Rotkiewicz A1 - Jeffrey Skolnick A1 - Andrzej Koliński KW - Amino Acid Sequence KW - Binding Sites KW - Hydrogen Bonding KW - Models KW - Molecular KW - Peptide Fragments KW - Peptide Fragments: chemistry KW - Protein Conformation KW - Protein Structure KW - Proteins KW - Proteins: chemistry KW - Secondary AB - Recently developed reduced models of proteins with knowledge-based force fields have been applied to a specific case of comparative modeling. From twenty high resolution protein structures of various structural classes, significant fragments of their chains have been removed and treated as unknown. The remaining portions of the structures were treated as fixed - i.e., as templates with an exact alignment. Then, the missed fragments were reconstructed using several modeling tools. These included three reduced types of protein models: the lattice SICHO (Side Chain Only) model, the lattice CABS (Calpha + Cbeta + Side group) model and an off-lattice model similar to the CABS model and called REFINER. The obtained reduced models were compared with more standard comparative modeling tools such as MODELLER and the SWISS-MODEL server. The reduced model results are qualitatively better for the higher resolution lattice models, clearly suggesting that these are now mature, competitive and complementary (in the range of sparse alignments) to the classical tools of comparative modeling. Comparison between the various reduced models strongly suggests that the essential ingredient for the sucessful and accurate modeling of protein structures is not the representation of conformational space (lattice, off-lattice, all-atom) but, rather, the specificity of the force fields used and, perhaps, the sampling techniques employed. These conclusions are encouraging for the future application of the fast reduced models in comparative modeling on a genomic scale. VL - 17 UR - http://www.ncbi.nlm.nih.gov/pubmed/15072433 ER - TY - JOUR T1 - A simple lattice model that exhibits a protein-like cooperative all-or-none folding transition JF - Biopolymers Y1 - 2003 A1 - Andrzej Koliński A1 - Dominik Gront A1 - Piotr Pokarowski A1 - Jeffrey Skolnick KW - Biopolymers KW - Biopolymers: chemistry KW - Biopolymers: metabolism KW - Chemical KW - Models KW - Molecular KW - Monte Carlo Method KW - Protein Folding KW - Protein Structure KW - Proteins KW - Proteins: chemistry KW - Proteins: metabolism KW - Secondary KW - Thermodynamics AB - In a recent paper (D. Gront et al., Journal of Chemical Physics, Vol. 115, pp. 1569, 2001) we applied a simple combination of the Replica Exchange Monte Carlo and the Histogram methods in the computational studies of a simplified protein lattice model containing hydrophobic and polar units and sequence-dependent local stiffness. A well-defined, relatively complex Greek-key topology, ground (native) conformations was found; however, the cooperativity of the folding transition was very low. Here we describe a modified minimal model of the same Greek-key motif for which the folding transition is very cooperative and has all the features of the "all-or-none" transition typical of real globular proteins. It is demonstrated that the all-or-none transition arises from the interplay between local stiffness and properly defined tertiary interactions. The tertiary interactions are directional, mimicking the packing preferences seen in proteins. The model properties are compared with other minimal protein-like models, and we argue that the model presented here captures essential physics of protein folding (structurally well-defined protein-like native conformation and cooperative all-or-none folding transition). VL - 69 UR - http://www.ncbi.nlm.nih.gov/pubmed/12833266 ER - TY - JOUR T1 - Solvent polarity and hydrogen-bonding effects on the nitrogen NMR shieldings of N-nitrosamines and DFT calculations of the shieldings of C-, N-, and O-nitroso systems JF - Journal of Magnetic Resonance Y1 - 2003 A1 - Michal Witanowski A1 - Zenobia Biedrzycka A1 - Wanda Sicinska A1 - Zbigniew Grabowski KW - Algorithms KW - Binding Sites KW - Carbon KW - Computer Simulation KW - Hydrogen Bonding KW - Macromolecular Substances KW - Magnetic Resonance Spectroscopy KW - Models, Molecular KW - Molecular Conformation KW - Molecular Structure KW - Nitrogen KW - Nitrogen Isotopes KW - Nitrosamines KW - Nitroso Compounds KW - Oxygen KW - solutions KW - Solvents AB - High-precision nitrogen NMR shieldings, bulk susceptibility corrected, are reported for dimethyl-N-nitrosamine (I) and diethyl-N-nitrosamine (II) in a variety of solvents which represent a wide range of solvent properties from the point of view of polarity as well as hydrogen bond donor and acceptor strength. The observed range of solvent-induced nitrogen shielding variations of (I) and (II) is significant for the amino-type nitrogens, up to about 16 ppm, and originates essentially from the deshielding effect of the increasing polarity of solvent. On the other side, the nitroso nitrogen shieldings reveal an even stronger response to solvent effects, within about 20 ppm, but in this case the increasing polarity and hydrogen bond donor strength of solvent produce enhanced shielding. DFT quantum-mechanical calculations using the GIAO/B3PW91/6-311++G** approach and geometry optimizations employing the same basis set and hybrid density functionals show an excellent correlation with the experimental data on C-, N-, and O-nitroso moieties and reproduce not only major changes but also most of the subtle variations in the experimental nitrogen shieldings of the nitroso systems as a whole. A combination of the calculations involving the corresponding N and O-protonated species and the trends observed in the solvent-induced nitrogen shielding variations shows clearly that the prime acceptor site for hydrogen bonding is the nitroso oxygen atom. VL - 164 IS - 2 ER - TY - JOUR T1 - TOUCHSTONE: a unified approach to protein structure prediction. JF - Proteins Y1 - 2003 A1 - Jeffrey Skolnick A1 - Zhang, Yang A1 - Arakaki, Adrian K A1 - Andrzej Koliński A1 - Michal Boniecki A1 - Szilágyi, András A1 - Daisuke Kihara KW - Algorithms KW - Models KW - Molecular KW - Protein Conformation KW - Protein Structure KW - Proteins KW - Proteins: chemistry KW - Secondary KW - Tertiary AB - We have applied the TOUCHSTONE structure prediction algorithm that spans the range from homology modeling to ab initio folding to all protein targets in CASP5. Using our threading algorithm PROSPECTOR that does not utilize input from metaservers, one threads against a representative set of PDB templates. If a template is significantly hit, Generalized Comparative Modeling designed to span the range from closely to distantly related proteins from the template is done. This involves freezing the aligned regions and relaxing the remaining structure to accommodate insertions or deletions with respect to the template. For all targets, consensus predicted side chain contacts from at least weakly threading templates are pooled and incorporated into ab initio folding. Often, TOUCHSTONE performs well in the CM to FR categories, with PROSPECTOR showing significant ability to identify analogous templates. When ab initio folding is done, frequently the best models are closer to the native state than the initial template. Among the particularly good predictions are T0130 in the CM/FR category, T0138 in the FR(H) category, T0135 in the FR(A) category, T0170 in the FR/NF category and T0181 in the NF category. Improvements in the approach are needed in the FR/NF and NF categories. Nevertheless, TOUCHSTONE was one of the best performing algorithms over all categories in CASP5. VL - CASP Suppl UR - http://www.ncbi.nlm.nih.gov/pubmed/14579335 ER - TY - JOUR T1 - TOUCHSTONE II: a new approach to ab initio protein structure prediction JF - Biophysical Journal Y1 - 2003 A1 - Yang Zhang A1 - Andrzej Koliński A1 - Jeffrey Skolnick KW - Algorithms KW - Amino Acid Sequence KW - Computer Simulation KW - Crystallography KW - Crystallography: methods KW - Energy Transfer KW - Models KW - Molecular KW - Molecular Sequence Data KW - Protein KW - Protein Conformation KW - Protein Folding KW - Protein Structure KW - Protein: methods KW - Proteins KW - Proteins: chemistry KW - Secondary KW - Sequence Analysis KW - Software KW - Static Electricity KW - Statistical AB - We have developed a new combined approach for ab initio protein structure prediction. The protein conformation is described as a lattice chain connecting C(alpha) atoms, with attached C(beta) atoms and side-chain centers of mass. The model force field includes various short-range and long-range knowledge-based potentials derived from a statistical analysis of the regularities of protein structures. The combination of these energy terms is optimized through the maximization of correlation for 30 x 60,000 decoys between the root mean square deviation (RMSD) to native and energies, as well as the energy gap between native and the decoy ensemble. To accelerate the conformational search, a newly developed parallel hyperbolic sampling algorithm with a composite movement set is used in the Monte Carlo simulation processes. We exploit this strategy to successfully fold 41/100 small proteins (36 approximately 120 residues) with predicted structures having a RMSD from native below 6.5 A in the top five cluster centroids. To fold larger-size proteins as well as to improve the folding yield of small proteins, we incorporate into the basic force field side-chain contact predictions from our threading program PROSPECTOR where homologous proteins were excluded from the data base. With these threading-based restraints, the program can fold 83/125 test proteins (36 approximately 174 residues) with structures having a RMSD to native below 6.5 A in the top five cluster centroids. This shows the significant improvement of folding by using predicted tertiary restraints, especially when the accuracy of side-chain contact prediction is >20%. For native fold selection, we introduce quantities dependent on the cluster density and the combination of energy and free energy, which show a higher discriminative power to select the native structure than the previously used cluster energy or cluster size, and which can be used in native structure identification in blind simulations. These procedures are readily automated and are being implemented on a genomic scale. VL - 85 UR - http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1303233&tool=pmcentrez&rendertype=abstract ER - TY - JOUR T1 - TOUCHSTONEX: protein structure prediction with sparse NMR data JF - Proteins Y1 - 2003 A1 - Wei Li A1 - Yang Zhang A1 - Daisuke Kihara A1 - Yuanpeng Janet Huang A1 - Deyou Zheng A1 - Gaetano T. Montelione A1 - Andrzej Koliński A1 - Jeffrey Skolnick KW - Algorithms KW - Amino Acids KW - Models, Molecular KW - Nuclear Magnetic Resonance, Biomolecular KW - Protein Conformation KW - Protein Folding KW - Protein Structure, Tertiary KW - Proteins KW - Staphylococcal Protein A AB - TOUCHSTONEX, a new method for folding proteins that uses a small number of long-range contact restraints derived from NMR experimental NOE (nuclear Overhauser enhancement) data, is described. The method employs a new lattice-based, reduced model of proteins that explicitly represents C(alpha), C(beta), and the sidechain centers of mass. The force field consists of knowledge-based terms to produce protein-like behavior, including various short-range interactions, hydrogen bonding, and one-body, pairwise, and multibody long-range interactions. Contact restraints were incorporated into the force field as an NOE-specific pairwise potential. We evaluated the algorithm using a set of 125 proteins of various secondary structure types and lengths up to 174 residues. Using N/8 simulated, long-range sidechain contact restraints, where N is the number of residues, 108 proteins were folded to a C(alpha)-root-mean-square deviation (RMSD) from native below 6.5 A. The average RMSD of the lowest RMSD structures for all 125 proteins (folded and unfolded) was 4.4 A. The algorithm was also applied to limited experimental NOE data generated for three proteins. Using very few experimental sidechain contact restraints, and a small number of sidechain-main chain and main chain-main chain contact restraints, we folded all three proteins to low-to-medium resolution structures. The algorithm can be applied to the NMR structure determination process or other experimental methods that can provide tertiary restraint information, especially in the early stage of structure determination, when only limited data are available. VL - 53 IS - 2 ER - TY - JOUR T1 - Unfolding of globular proteins: monte carlo dynamics of a realistic reduced model JF - Biophysical Journal Y1 - 2003 A1 - Andrzej Koliński A1 - Piotr Klein A1 - Piotr Romiszowski A1 - Jeffrey Skolnick KW - Apoproteins KW - Apoproteins: chemistry KW - Bacterial Proteins KW - Chemical KW - DNA-Binding Proteins KW - DNA-Binding Proteins: chemistry KW - Leghemoglobin KW - Leghemoglobin: chemistry KW - Models KW - Molecular KW - Monte Carlo Method KW - Myoglobin KW - Myoglobin: chemistry KW - Nerve Tissue Proteins KW - Nerve Tissue Proteins: chemistry KW - Plastocyanin KW - Plastocyanin: chemistry KW - Protein Denaturation KW - Protein Folding KW - Proteins KW - Proteins: chemistry KW - Statistical AB - Reduced lattice models of proteins and Monte Carlo dynamics were used to simulate the initial stages of the unfolding of several proteins of various structural types, and the results were compared to experiment. The models semiquantitatively reproduce the approximate order of events of unfolding as well as subtle mutation effects and effects resulting from differences in sequences of similar folds. The short-time mobility of particular residues, observed in simulations, correlates with the crystallographic temperature factor. The main factor controlling unfolding is the native state topology, with sequence playing a less important role. The correlation with various experiments, especially for sequence-specific effects, strongly suggests that properly designed reduced models of proteins can be used for qualitative studies (or prediction) of protein unfolding pathways. VL - 85 UR - http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1303603&tool=pmcentrez&rendertype=abstract ER - TY - JOUR T1 - Use of residual dipolar couplings as restraints in ab initio protein structure prediction JF - Biopolymers Y1 - 2003 A1 - Turkan Haliloglu A1 - Andrzej Koliński A1 - Jeffrey Skolnick KW - ab initio structure prediction KW - dynamic modes KW - residual dipolar coupling KW - sicho model AB - NMR residual dipolar couplings (RDCs), in the form of the projection angles between the respective internuclear bond vectors, are used as structural restraints in the ab initio structure prediction of a test set of six proteins. The restraints are applied using a recently developed SICHO (SIde-CHain-Only) lattice protein model that employs a replica exchange Monte Carlo (MC) algorithm to search conformational space. Using a small number of RDC restraints, the quality of the predicted structures is improved as reflected by lower RMSD/dRMSD (root mean square distance root mean square deviation) values from the corresponding native structures and by the higher correlation of the most cooperative mode of motion of each predicted structure with that of the native structure. The latter, in particular, has possible implications for the structurebased functional analysis of predicted structures. VL - 70 UR - http://onlinelibrary.wiley.com/doi/10.1002/bip.10511/full ER - TY - JOUR T1 - 2-Ethyl and 2-ethylidene analogues of 1alpha,25-dihydroxy-19-norvitamin D(3): synthesis, conformational analysis, biological activities, and docking to the modeled rVDR ligand binding domain. JF - Journal of Medicinal Chemistry Y1 - 2002 A1 - Rafal R. Sicinski A1 - Piotr Rotkiewicz A1 - Andrzej Koliński A1 - Wanda Sicinska A1 - Jean M. Prahl A1 - Connie M. Smith A1 - Hector F. DeLuca KW - Animals KW - Binding Sites KW - Biological Transport KW - Calcitriol KW - Calcium KW - Cell Differentiation KW - Chromatography, High Pressure Liquid KW - HL-60 Cells KW - Humans KW - Intestinal Mucosa KW - Ligands KW - Magnetic Resonance Spectroscopy KW - Male KW - Models, Molecular KW - Molecular Conformation KW - Rats KW - Receptors, Calcitriol KW - Spectrophotometry, Ultraviolet KW - Structure-Activity Relationship KW - Swine AB - Novel 19-nor analogues of 1alpha,25-dihydroxyvitamin D(3) were prepared and substituted at C-2 with an ethylidene group. The synthetic pathway was via Wittig-Horner coupling of the corresponding A-ring phosphine oxides with the protected 25-hydroxy Grundmann's ketones. Selective catalytic hydrogenation of 2-ethylidene analogues provided the 2alpha- and 2beta-ethyl compounds. The 2-ethylidene-19-nor compounds with a methyl group from the ethylidene moiety in a trans relationship to the C(6)-C(7) bond (E-isomers) were more potent than the corresponding Z-isomers and the natural hormone in binding to the vitamin D receptor. Both geometrical isomers (E and Z) of (20S)-2-ethylidene-19-norvitamin D(3) and both 2alpha-ethyl-19-norvitamins (in the 20R- and 20S-series) have much higher HL-60 differentiation activity than does 1alpha,25-(OH)(2)D(3). Both E-isomers (20R and 20S) of 2-ethylidene vitamins are characterized by very high calcemic activity in rats. The three-dimensional structure model of the rat vitamin D receptor and the computational docking of four synthesized (20R)-19-norvitamin D(3) analogues into its binding pocket are also reported. VL - 45 IS - 16 ER - TY - JOUR T1 - Ab initio protein structure prediction on a genomic scale: application to the Mycoplasma genitalium genome JF - Proceedings of the National Academy of Sciences of the United States of America Y1 - 2002 A1 - Daisuke Kihara A1 - Yang Zhang A1 - Hui Lu A1 - Andrzej Koliński A1 - Jeffrey Skolnick KW - Algorithms KW - Bacterial KW - Databases as Topic KW - Genome KW - Models KW - Molecular KW - Monte Carlo Method KW - Mycoplasma KW - Mycoplasma: genetics KW - Protein Folding KW - Proteins KW - Proteins: chemistry KW - Software AB - An ab initio protein structure prediction procedure, TOUCHSTONE, was applied to all 85 small proteins of the Mycoplasma genitalium genome. TOUCHSTONE is based on a Monte Carlo refinement of a lattice model of proteins, which uses threading-based tertiary restraints. Such restraints are derived by extracting consensus contacts and local secondary structure from at least weakly scoring structures that, in some cases, can lack any global similarity to the sequence of interest. Selection of the native fold was done by using the convergence of the simulation from two different conformational search schemes and the lowest energy structure by a knowledge-based atomic-detailed potential. Among the 85 proteins, for 34 proteins with significant threading hits, the template structures were reasonably well reproduced. Of the remaining 51 proteins, 29 proteins converged to five or fewer clusters. In the test set, 84.8% of the proteins that converged to five or fewer clusters had a correct fold among the clusters. If this statistic is simply applied, 24 proteins (84.8% of the 29 proteins) may have correct folds. Thus, the topology of a total of 58 proteins probably has been correctly predicted. Based on these results, ab initio protein structure prediction is becoming a practical approach. VL - 99 UR - http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=122890&tool=pmcentrez&rendertype=abstract ER - TY - JOUR T1 - Computer simulations of protein folding with a small number of distance restraints JF - Acta Biochimica Polonica Y1 - 2002 A1 - Andrzej Sikorski A1 - Andrzej Koliński A1 - Jeffrey Skolnick KW - Algorithms KW - Amino Acids KW - Amino Acids: chemistry KW - Chemical KW - Computer Simulation KW - Hydrogen Bonding KW - Models KW - Molecular KW - Monte Carlo Method KW - Nerve Tissue Proteins KW - Nerve Tissue Proteins: chemistry KW - Plastocyanin KW - Plastocyanin: chemistry KW - Protein Conformation KW - Protein Folding KW - Protein Kinases KW - Thermodynamics AB - A high coordination lattice model was used to represent the protein chain. Lattice points correspond to amino-acid side groups. A complicated force field was designed in order to reproduce a protein-like behavior of the chain. Long-distance tertiary restraints were also introduced into the model. The Replica Exchange Monte Carlo method was applied to find the lowest energy states of the folded chain and to solve the problem of multiple minima. In this method, a set of replicas of the model chain was simulated independently in different temperatures with the exchanges of replicas allowed. The model chains, which consisted of up to 100 residues, were folded to structures whose root-mean-square deviation (RMSD) from their native state was between 2.5 and 5 A. Introduction of restrain based on the positions of the backbone hydrogen atoms led to an improvement in the number of successful simulation runs. A small improvement (about 0.5 A) was also achieved in the RMSD of the folds. The proposed method can be used for the refinement of structures determined experimentally from NMR data. VL - 49 UR - http://www.ncbi.nlm.nih.gov/pubmed/12422238 ER - TY - JOUR T1 - Numerical study of the entropy loss of dimerization and the folding thermodynamics of the GCN4 leucine zipper JF - Biophysical Journal Y1 - 2002 A1 - Jorge Viñals A1 - Andrzej Koliński A1 - Jeffrey Skolnick KW - Biophysical Phenomena KW - Biophysics KW - Databases as Topic KW - Dimerization KW - DNA-Binding Proteins KW - DNA-Binding Proteins: chemistry KW - Entropy KW - Hot Temperature KW - Leucine Zippers KW - Models KW - Monte Carlo Method KW - Protein Folding KW - Protein Kinases KW - Protein Kinases: chemistry KW - Saccharomyces cerevisiae Proteins KW - Saccharomyces cerevisiae Proteins: chemistry KW - Temperature KW - Theoretical KW - Thermodynamics AB - A lattice-based model of a protein and the Monte Carlo simulation method are used to calculate the entropy loss of dimerization of the GCN4 leucine zipper. In the representation used, a protein is a sequence of interaction centers arranged on a cubic lattice, with effective interaction potentials that are both of physical and statistical nature. The Monte Carlo simulation method is then used to sample the partition functions of both the monomer and dimer forms as a function of temperature. A method is described to estimate the entropy loss upon dimerization, a quantity that enters the free energy difference between monomer and dimer, and the corresponding dimerization reaction constant. As expected, but contrary to previous numerical studies, we find that the entropy loss of dimerization is a strong function of energy (or temperature), except in the limit of large energies in which the motion of the two dimer chains becomes largely uncorrelated. At the monomer-dimer transition temperature we find that the entropy loss of dimerization is approximately five times smaller than the value that would result from ideal gas statistics, a result that is qualitatively consistent with a recent experimental determination of the entropy loss of dimerization of a synthetic peptide that also forms a two-stranded alpha-helical coiled coil. VL - 83 UR - http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1302364&tool=pmcentrez&rendertype=abstract ER - TY - JOUR T1 - The protein folding problem: a biophysical enigma JF - Current Pharmaceutical Biotechnology Y1 - 2002 A1 - Jacquelyn S. Fetrow A1 - A. Giammona A1 - Andrzej Koliński A1 - Jeffrey Skolnick KW - Animals KW - Biophysical Phenomena KW - Biophysics KW - Computational Biology KW - Computational Biology: methods KW - Computational Biology: trends KW - Humans KW - Protein Folding AB - Protein folding, the problem of how an amino acid sequence folds into a unique three-dimensional shape, has been a long-standing problem in biology. The success of genome-wide sequencing efforts has increased the interest in understanding the protein folding enigma, because realizing the value of the genomic sequences rests on the accuracy with which the encoded gene products are understood. Although a complete understanding of the kinetics and thermodynamics of protein folding has remained elusive, there has been considerable progress in techniques to predict protein structure from amino acid sequences. The prediction techniques fall into three general classes: comparative modeling, threading and ab initio folding. The current state of research in each of these three areas is reviewed here in detail. Efforts to apply each method to proteome-wide analysis are reviewed, and some of the key technical hurdles that remain are presented. Protein folding technologies, while not yet providing a full understanding of the protein folding process, have clearly progressed to the point of being useful in enabling structure-based annotation of genomic sequences. VL - 3 UR - http://www.ncbi.nlm.nih.gov/pubmed/12463416 ER - TY - JOUR T1 - A study of solvent polarity and hydrogen bonding effects on the nitrogen NMR shieldings of N-nitramines and ab initio calculations of the nitrogen shieldings of C-nitro, N-nitro and O-nitro systems JF - Journal of Molecular Structure Y1 - 2002 A1 - Michal Witanowski A1 - Zenobia Biedrzycka A1 - Wanda Sicinska A1 - Zbigniew Grabowski KW - Ab initio calculations KW - Hydrogen Bonding KW - N-nitramines KW - Nitrogen NMR shieldings KW - Solvent effects AB - High-precision nitrogen NMR shieldings, bulk susceptibility corrected, are reported for dimethylnitramine (1) and diethylnitramine (2) in a variety of solvents which represent a wide range of solvent properties from the point of view of polarity as well as hydrogen bond donor and acceptor strength. The observed range of solvent-induced nitrogen shielding variations of 1 and 2 is significant for the amino-type nitrogens, up to about 10 ppm, and originates essentially from the deshielding effect of the increasing polarity of solvent. On the other side, the nitro nitrogens reveal a very weak and rather chaotic response to solvent effects, within about 2 ppm. This is in a sharp contrast with the behavior of the nitrogen shieldings of C-nitro and O-nitro groups where solvent effects induce variations within at least 6 ppm which follow a regular pattern of enhanced magnetic deshielding with increasing polarity involved. This apparent insensitivity of the N-nitro group shielding to solvent effects seems to stem from the cancellation of opposite effects, the shielding effect of the electron charge migration to the nitro group upon increasing solvent polarity, and the deshielding effect produced by the flattening of the pyramidal arrangement of bonds at the amino nitrogen with the increasing polarity of the medium. Ab initio quantum-mechanical calculations using the View the MathML source approach and geometry optimizations employing the same basis set and density functionals show an excellent linear correlation with the experimental data and reproduce not only major changes but also most of the subtle variations in the experimental nitrogen shieldings of the nitro systems as a whole. VL - 602–603 UR - http://www.sciencedirect.com/science/article/pii/S0022286001007347 ER - TY - JOUR T1 - A unified approach to the prediction of protein structure and function JF - Advances in Chemical Physics Y1 - 2002 A1 - Jeffrey Skolnick A1 - Andrzej Koliński VL - 120 UR - http://books.google.com/books?hl=en&lr=&id=FBhtodr1Ei8C&oi=fnd&pg=PA131&dq=a+unified+approach+to+the+prediction+of+protein+structure+and+function&ots=Fo3gV4RieR&sig=hZW2mXWR2\_yKXTARCuukSOERnoY ER - TY - CHAP T1 - A unified approach to the prediction of protein structure and function T2 - Computational Methods for Protein Folding Y1 - 2002 A1 - Jeffrey Skolnick A1 - Andrzej Koliński KW - ab initio folding KW - atomic models KW - biochemical function KW - comparative models KW - ligand identification KW - low-resolution structures KW - Protein Structure KW - reduced models KW - threading KW - unified folding scheme AB - The major focus of this review is to describe a unified approach to protein structure prediction that reduces to threading plus structure refinement when an example of the probe sequence is found; but if not, it incorporates information from weakly significant probe sequence-template structure matches and then does ab initio folding with the structural information gleaned from such matches. It has the advantage that it can predict a novel fold even though some of the information comes from threading on already solved structures. JF - Computational Methods for Protein Folding VL - 120 ER - TY - JOUR T1 - Ab initio protein structure prediction via a combination of threading, lattice folding, clustering, and structure refinement JF - Proteins Y1 - 2001 A1 - Jeffrey Skolnick A1 - Andrzej Koliński A1 - Daisuke Kihara A1 - Marcos Betancourt A1 - Piotr Rotkiewicz A1 - Michal Boniecki KW - carlo methods KW - casp4 KW - lattice models KW - monte KW - Protein Folding KW - protein struc- KW - structure KW - threading KW - ture prediction AB - A combination of sequence comparison, threading, lattice, and off-lattice Monte Carlo (MC) simulations and clustering of MC trajectories was used to predict the structure of all (but one) targets of the CASP4 experiment on protein structure prediction. Although this method is automated and is operationally the same regardless of the level of uniqueness of the query proteins, here we focus on the more difficult targets at the border of the fold recognition and newfold categories. For a few targets (T0110 is probably the best example), the ab initio method produced more accurate models than models obtained by the fold recognition techniques. For the most difficult targets from the newfold categories, substantial fragments of structures have been correctly predicted. Possible improvements of the method are briefly discussed. VL - 45 UR - http://onlinelibrary.wiley.com/doi/10.1002/prot.1172/full IS - Suppl. S5 CASP4 ER - TY - JOUR T1 - Computational studies of protein folding JF - Computing in Science & Engineering Y1 - 2001 A1 - Jeffrey Skolnick A1 - Andrzej Koliński AB - The authors describe the state of the art in the field of protein structure prediction. They also introduce Prospector, a newly developed, iterative threading algorithm for protein structure prediction that can also be applied to ab initio protein folding, and discuss the promising results of its large-scale application. VL - September/October UR - http://www.annualreviews.org/doi/pdf/10.1146/annurev.bb.25.060196.001531 ER - TY - JOUR T1 - Generalized comparative modeling (GENECOMP): a combination of sequence comparison, threading, and lattice modeling for protein structure prediction and refinement JF - Proteins Y1 - 2001 A1 - Andrzej Koliński A1 - Marcos Betancourt A1 - Daisuke Kihara A1 - Piotr Rotkiewicz A1 - Jeffrey Skolnick KW - Algorithms KW - Chemical KW - Combinatorial Chemistry Techniques KW - Combinatorial Chemistry Techniques: methods KW - Computational Biology KW - Computational Biology: methods KW - Computer Simulation KW - Databases KW - Factual KW - Models KW - Molecular KW - Monte Carlo Method KW - Protein Folding KW - Proteins KW - Proteins: chemistry KW - Sequence Alignment KW - Sequence Alignment: methods AB - An improved generalized comparative modeling method, GENECOMP, for the refinement of threading models is developed and validated on the Fischer database of 68 probe-template pairs, a standard benchmark used to evaluate threading approaches. The basic idea is to perform ab initio folding using a lattice protein model, SICHO, near the template provided by the new threading algorithm PROSPECTOR. PROSPECTOR also provides predicted contacts and secondary structure for the template-aligned regions, and possibly for the unaligned regions by garnering additional information from other top-scoring threaded structures. Since the lowest-energy structure generated by the simulations is not necessarily the best structure, we employed two structure-selection protocols: distance geometry and clustering. In general, clustering is found to generate somewhat better quality structures in 38 of 68 cases. When applied to the Fischer database, the protocol does no harm and in a significant number of cases improves upon the initial threading model, sometimes dramatically. The procedure is readily automated and can be implemented on a genomic scale. VL - 44 UR - http://www.ncbi.nlm.nih.gov/pubmed/11391776 ER - TY - JOUR T1 - Model of three-dimensional structure of vitamin D receptor and its binding mechanism with 1alpha,25-dihydroxyvitamin D(3) JF - Proteins Y1 - 2001 A1 - Piotr Rotkiewicz A1 - Wanda Sicinska A1 - Andrzej Koliński A1 - Hector F. DeLuca KW - Amino Acid KW - Amino Acid Sequence KW - Animals KW - Binding Sites KW - Calcitriol KW - Calcitriol: chemistry KW - Calcitriol: genetics KW - Computational Biology KW - Humans KW - Ligands KW - Models KW - Molecular KW - Molecular Sequence Data KW - Point Mutation KW - Protein Conformation KW - Protein Structure KW - Rats KW - Receptors KW - Sequence Homology KW - Tertiary AB - Comparative modeling of the vitamin D receptor three-dimensional structure and computational docking of 1alpha,25-dihydroxyvitamin D(3) into the putative binding pocket of the two deletion mutant receptors: (207-423) and (120-422, Delta [164-207]) are reported and evaluated in the context of extensive mutagenic analysis and crystal structure of holo hVDR deletion protein published recently. The obtained molecular model agrees well with the experimentally determined structure. Six different conformers of 1alpha,25-dihydroxyvitamin D(3) were used to study flexible docking to the receptor. On the basis of values of conformational energy of various complexes and their consistency with functional activity, it appears that 1alpha,25-dihydroxyvitamin D(3) binds the receptor in its 6-s-trans form. The two lowest energy complexes obtained from docking the hormone into the deletion protein (207-423) differ in conformation of ring A and orientation of the ligand molecule in the VDR pocket. 1alpha,25-Dihydroxyvitamin D(3) possessing the A-ring conformation with axially oriented 1alpha-hydroxy group binds receptor with its 25-hydroxy substituent oriented toward the center of the receptor cavity, whereas ligand possessing equatorial conformation of 1alpha-hydroxy enters the pocket with A ring directed inward. The latter conformation and orientation of the ligand is consistent with the crystal structure of hVDR deletion mutant (118-425, Delta [165-215]). The lattice model of rVDR (120-422, Delta [164-207]) shows excellent agreement with the crystal structure of the hVDR mutant. The complex obtained from docking the hormone into the receptor has lower energy than complexes for which homology modeling was used. Thus, a simple model of vitamin D receptor with the first two helices deleted can be potentially useful for designing a general structure of ligand, whereas the advanced lattice model is suitable for examining binding sites in the pocket. VL - 44 UR - http://www.ncbi.nlm.nih.gov/pubmed/11455592 ER - TY - JOUR T1 - A new combination of replica exchange Monte Carlo and histogram analysis for protein folding and thermodynamics JF - The Journal of Chemical Physics Y1 - 2001 A1 - Dominik Gront A1 - Andrzej Koliński A1 - Jeffrey Skolnick AB - A novel combination of replica exchange Monte Carlo sampling techniques with a histogram analysis approach is developed and applied to study the thermodynamics of the folding transition in a face-centered cubic lattice chain protein model. Sequences of hydrophobic (H) and polar (P) topology residues were designed to fold into various b-barrel type proteins. The interaction scheme includes the short-range propensity to form extended conformations, residue-dependent long-range contact potentials, and orientation-dependent hydrogen bonds. Weakly cooperative folding transitions could be observed for properly designed HP. (Hydrophobic and polar residue sequences with cooperative long-range interaction methods were proposed and tested.) Based on the study of these systems, the computational cost of such an approach is many times less than the cost of other Monte Carlo procedures. This opens up the possibility for efficient studies of the folding thermodynamics of more detailed protein models. VL - 115 UR - http://link.aip.org/link/JCPSA6/v115/i3/p1569/s1&Agg=doi ER - TY - JOUR T1 - Structure of proteins: New approach to molecular modeling JF - Polish Journal of Chemistry Y1 - 2001 A1 - Andrzej Koliński A1 - Piotr Rotkiewicz A1 - Jeffrey Skolnick KW - comperative modeling KW - lattice protein models KW - loop modeling KW - Monte Carlo simulations KW - Protein Folding KW - protein structure prediction VL - 75 UR - http://baztech.icm.edu.pl/baztech/cgi-bin/btgetdoc.cgi?BUJ1-0017-0036 ER - TY - JOUR T1 - Three-dimensional modeling of the I-TevI homing endonuclease catalytic domain, a GIY-YIG superfamily member, using NMR restraints and Monte Carlo dynamics JF - Protein Engineering Y1 - 2001 A1 - Janusz M. Bujnicki A1 - Piotr Rotkiewicz A1 - Andrzej Koliński A1 - Leszek Rychlewski KW - Algorithms KW - Binding Sites KW - Biomolecular KW - Endodeoxyribonucleases KW - Endodeoxyribonucleases: chemistry KW - Models KW - Molecular KW - Monte Carlo Method KW - Nuclear Magnetic Resonance KW - Protein Structure KW - Sequence Alignment KW - Tertiary AB - Using a recent version of the SICHO algorithm for in silico protein folding, we made a blind prediction of the tertiary structure of the N-terminal, independently folded, catalytic domain (CD) of the I-TevI homing endonuclease, a representative of the GIY-YIG superfamily of homing endonucleases. The secondary structure of the I-TevI CD has been determined using NMR spectroscopy, but computational sequence analysis failed to detect any protein of known tertiary structure related to the GIY-YIG nucleases (Kowalski et al., Nucleic Acids Res., 1999, 27, 2115-2125). To provide further insight into the structure-function relationships of all GIY-YIG superfamily members, including the recently described subfamily of type II restriction enzymes (Bujnicki et al., Trends Biochem. Sci., 2000, 26, 9-11), we incorporated the experimentally determined and predicted secondary and tertiary restraints in a reduced (side chain only) protein model, which was minimized by Monte Carlo dynamics and simulated annealing. The subsequently elaborated full atomic model of the I-TevI CD allows the available experimental data to be put into a structural context and suggests that the GIY-YIG domain may dimerize in order to bring together the conserved residues of the active site. VL - 14 UR - http://www.ncbi.nlm.nih.gov/pubmed/11739889 ER - TY - JOUR T1 - TOUCHSTONE: an ab initio protein structure prediction method that uses threading-based tertiary restraints JF - Proceedings of the National Academy of Sciences of the United States of America Y1 - 2001 A1 - Daisuke Kihara A1 - Hui Lu A1 - Andrzej Koliński A1 - Jeffrey Skolnick KW - Algorithms KW - Computer Simulation KW - Models KW - Molecular KW - Monte Carlo Method KW - Protein Folding KW - Protein Structure KW - Proteins KW - Proteins: chemistry KW - Tertiary AB - The successful prediction of protein structure from amino acid sequence requires two features: an efficient conformational search algorithm and an energy function with a global minimum in the native state. As a step toward addressing both issues, a threading-based method of secondary and tertiary restraint prediction has been developed and applied to ab initio folding. Such restraints are derived by extracting consensus contacts and local secondary structure from at least weakly scoring structures that, in some cases, can lack any global similarity to the sequence of interest. Furthermore, to generate representative protein structures, a reduced lattice-based protein model is used with replica exchange Monte Carlo to explore conformational space. We report results on the application of this methodology, termed TOUCHSTONE, to 65 proteins whose lengths range from 39 to 146 residues. For 47 (40) proteins, a cluster centroid whose rms deviation from native is below 6.5 (5) A is found in one of the five lowest energy centroids. The number of correctly predicted proteins increases to 50 when atomic detail is added and a knowledge-based atomic potential is combined with clustered and nonclustered structures for candidate selection. The combination of the ratio of the relative number of contacts to the protein length and the number of clusters generated by the folding algorithm is a reliable indicator of the likelihood of successful fold prediction, thereby opening the way for genome-scale ab initio folding. VL - 98 UR - http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=56926&tool=pmcentrez&rendertype=abstract ER - TY - JOUR T1 - Accurate reconstruction of all-atom protein representations from side-chain-based low-resolution models JF - Proteins Y1 - 2000 A1 - M. Feig A1 - Piotr Rotkiewicz A1 - Andrzej Koliński A1 - Jeffrey Skolnick A1 - Charles L. Brooks III KW - Models KW - Molecular KW - Proteins KW - Proteins: chemistry AB - A procedure for the reconstruction of all-atom protein structures from side-chain center-based low-resolution models is introduced and applied to a set of test proteins with high-resolution X-ray structures. The accuracy of the rebuilt all-atom models is measured by root mean square deviations to the corresponding X-ray structures and percentages of correct chi(1) and chi(2) side-chain dihedrals. The benefit of including C(alpha) positions in the low-resolution model is examined, and the effect of lattice-based models on the reconstruction accuracy is discussed. Programs and scripts implementing the reconstruction procedure are made available through the NIH research resource for Multiscale Modeling Tools in Structural Biology (http://mmtsb.scripps.edu). VL - 41 UR - http://www.ncbi.nlm.nih.gov/pubmed/10944396 ER - TY - JOUR T1 - Combining MONSSTER and LES/PME to Predict Protein Structure from Amino Acid Sequence: Application to the Small Protein CMTI-1 JF - Journal of the American Chemical Society Y1 - 2000 A1 - Carlos Simmerling A1 - Matthew R. Lee A1 - Angel. R. Ortiz A1 - Andrzej Koliński A1 - Jeffrey Skolnick A1 - Peter A. Kollman AB - A combined method for the prediction of protein tertiary structures from sequence is presented. This multistep procedure initially uses a simplified approach to protein structure prediction, MONSSTER, that assembles structures from initial extended conformations and scores them. Then, using the lowest-energy low-resolution model as a starting conformation, a detailed atomic model is built and refined using molecular dynamics simulations that employ the locally enhanced sampling (LES) methodology with the particle mesh Ewald (PME) technique for calculation of long-range electrostatic interactions. The combined method is applied to a small disulfide-rich 29-residue protein CMTI-1, a trypsin inhibitor found in squash seeds. Starting with an initial low-resolution model from MONSSTER, which has an rmsd from the native conformation of 3.7 Å (5.0 Å) for Cα atoms (all heavy atoms), LES/PME refinement leads to a structure that is only 2.5 Å (3.3 Å) from native, with a Cα rmsd of only 1.7 Å for residues 5−29. These rmsd values should be compared to Cα rmsd values of 1.2 Å (all residues) or 0.8 Å (residues 5−29) found in PME molecular dynamics simulations that start with the native conformation. VL - 122 UR - http://pubs.acs.org/doi/abs/10.1021/ja993119k ER - TY - JOUR T1 - Comparison of three Monte Carlo conformational search strategies for a proteinlike homopolymer model: Folding thermodynamics and identification of low-energy JF - Journal of Chemical Physics Y1 - 2000 A1 - Dominik Gront A1 - Andrzej Koliński A1 - Jeffrey Skolnick AB - Entropy sampling Monte Carlo, the replica method, and the classical Metropolis scheme were applied in numerical studies of the collapse transition in a simple face-centered cubic lattice polymer. The force field of the model consists of pairwise, contact-type, long-range interactions and a short-range potential based on the β-sheet definition assumed in the model. The ability to find the lowest energy conformation by various Monte Carlo methods and the computational cost associated with each was examined. It is shown that all of the methods generally provide the same picture of the collapse transition. However, the most complete thermodynamic description of the transition derives from the results of entropy sampling Monte Carlo simulations, but this is the most time-consuming method. The replica method is shown to be the most effective and efficient in searching for the lowest energy conformation. The possible consequences of these findings for the development of simulation strategies for the folding of model proteins are discussed briefly. VL - 113 UR - http://smartech.gatech.edu/handle/1853/27030 ER - TY - JOUR T1 - Computer simulations of the properties of the alpha2, alpha2C, and alpha2D de novo designed helical proteins JF - Proteins Y1 - 2000 A1 - Andrzej Sikorski A1 - Andrzej Koliński A1 - Jeffrey Skolnick KW - Amino Acid Sequence KW - Computer Simulation KW - Drug Design KW - Molecular Sequence Data KW - Protein Folding KW - Protein Structure KW - Proteins KW - Proteins: chemistry KW - Secondary KW - Thermodynamics AB - Reduced lattice models of the three de novo designed helical proteins alpha2, alpha2C, and alpha2D were studied. Low temperature stable folds were obtained for all three proteins. In all cases, the lowest energy folds were four-helix bundles. The folding pathway is qualitatively the same for all proteins studied. The energies of various topologies are similar, especially for the alpha2 polypeptide. The simulated crossover from molten globule to native-like behavior is very similar to that seen in experimental studies. Simulations on a reduced protein model reproduce most of the experimental properties of the alpha2, alpha2C, and alpha2D proteins. Stable four-helix bundle structures were obtained, with increasing native-like behavior on-going from alpha2 to alpha2D that mimics experiment. VL - 38 UR - http://www.ncbi.nlm.nih.gov/pubmed/10651035 ER - TY - JOUR T1 - Derivation of protein-specific pair potentials based on weak sequence fragment similarity JF - Proteins: Structure, Function, Bioinformatics Y1 - 2000 A1 - Jeffrey Skolnick A1 - Andrzej Koliński A1 - Angel Ortiz KW - knowledge-based potentials KW - potential deriva- KW - Sequence Analysis KW - structure prediction KW - Tertiary KW - tion AB - A method is presented for the derivation of knowledge-based pair potentials that corrects for the various compositions of different proteins. The resulting statistical pair potential is more specific than that derived from previous approaches as assessed by gapless threading results. Additionally, a methodology is presented that interpolates between statistical potentials when no homologous examples to the protein of interest are in the structural database used to derive the potential, to a Go-like potential (in which native interactions are favorable and all nonnative interactions are not) when homologous proteins are present. For cases in which no protein exceeds 30% sequence identity, pairs of weakly homologous interacting fragments are employed to enhance the specificity of the potential. In gapless threading, the mean z score increases from -10.4 for the best statistical pair potential to -12.8 when the local sequence similarity, fragment-based pair potentials are used. Examination of the ab initio structure prediction of four representative globular proteins consistently reveals a qualitative improvement in the yield of structures in the 4 to 6 A rmsd from native range when the fragment-based pair potential is used relative to that when the quasichemical pair potential is employed. This suggests that such protein-specific potentials provide a significant advantage relative to generic quasichemical potentials. VL - 38 UR - http://onlinelibrary.wiley.com/doi/10.1002/(SICI)1097-0134(20000101)38:1%3C3::AID-PROT2%3E3.0.CO;2-S/full ER - TY - JOUR T1 - Helix-coil and beta sheet-coil transitions in a simplified, yet realistic protein model JF - Macromolecular Theory and Simulations Y1 - 2000 A1 - Bartosz Ilkowski A1 - Jeffrey Skolnick A1 - Andrzej Koliński AB -

A reduced model of polypeptide chains and protein stochastic dynamics is employed in Monte Carlo studies of the coil-globule transition. The model assumes a high-resolution lattice representation of protein conformational space. The interaction scheme is derived from a statistical analysis of structural regularities seen in known three-dimensional protein structures. It is shown that model polypeptides containing residues that have strong propensities towards locally expanded conformations collapse to β-like globular conformations, while polypeptides containing residues with helical propensities form globules of closely packed helices. A more cooperative transition is observed for β-type systems. It is also demonstrated that hydrogen bonding is an important factor for protein cooperativity, although, for systems with suppressed hydrogen bond interactions, a higher cooperativity of β-type proteins is also observed.

VL - 9 UR - http://doi.wiley.com/10.1002/1521-3919(20001101)9:8<523::AID-MATS523>3.0.CO;2-I IS - 8 ER - TY - JOUR T1 - Monte Carlo simulation of designed helical proteins JF - Acta Poloniae Pharmaceutica – Drug Research Y1 - 2000 A1 - Andrzej Sikorski A1 - Andrzej Koliński A1 - Jeffrey Skolnick KW - Monte Carlo Method KW - Protein Conformation KW - Protein Folding KW - Protein Structure, Secondary VL - 57 Suppl ER - TY - JOUR T1 - Nitrogen NMR shieldings of thiourea systems as a function of solvent polarity and hydrogen bond effects JF - Journal of Molecular Structure Y1 - 2000 A1 - Michal Witanowski A1 - Zenobia Biedrzycka A1 - Wanda Sicinska A1 - Graham A. Webb KW - 14N NMR KW - Ab initio molecular orbital calculations KW - Hydrogen-bonding KW - Solvent polarity KW - Thiourea systems AB - Tetramethylthiourea, 1, and thiourea, 2, have been studied in a wide variety of solvents by high-precision 14N NMR measurements. The chosen solvents exhibit a wide range of hydrogen-bonding and polarity/polarisability properties. The observed nitrogen shielding variations of the solutes, due to solvent change, are significant and are attributed to solvent polarity, solute to solvent and solvent to solute hydrogen-bonding effects. Nitrogen deshielding of 1 and 2 is produced by all these interactions, due to an enhanced delocalisation of the nitrogen lone-pair electron into the π systems of 1 and 2. The nitrogen NMR shieldings of 1 and 2 are calculated by the CHF–GIAO ab initio molecular orbital procedure using a 6-31++G** basis set. The calculations are for isolated molecules, and their results satisfactorily reproduce the position of the thiourea nitrogen resonance obtained in a dilute solution in cyclohexane with respect to that of urea systems and nitromethane. VL - 516 UR - http://www.sciencedirect.com/science/article/pii/S0022286099002021 ER - TY - JOUR T1 - Protein Folding: Flexible Lattice Models JF - Progress of Theoretical Physics Supplement Y1 - 2000 A1 - Andrzej Koliński A1 - Piotr Rotkiewicz A1 - Bartosz Ilkowski A1 - Jeffrey Skolnick AB - In the post genomic era a possibility of theoretical prediction of protein structure from sequence of amino acids is one of the most important and challenging goals of molecular biology. High complexity of the problem requires simplification of molecular models and very efficient computational tools. Proposed here model of protein structure, dynamics and interaction scheme assumes a single interaction center per amino acid residue. This highly simplified representation is supplemented by a number of build-in implicit packing rules that enable a reasonable modeling of protein geometry that is compatible with detailed atomic models. Preliminary applications to ab initio protein folding and distant homology comparative modeling are described and discussed. VL - 138 UR - http://ptp.ipap.jp/link?PTPS/138/292/ ER - TY - JOUR T1 - Structural genomics and its importance for gene function analysis JF - Nature Biotechnology Y1 - 2000 A1 - Jeffrey Skolnick A1 - Jacquelyn S. Fetrow A1 - Andrzej Koliński KW - Animals KW - Computer Simulation KW - Databases KW - Evolution KW - Factual KW - Genome KW - Humans KW - Internet KW - Molecular KW - Molecular Biology KW - Molecular Biology: methods KW - Protein Folding KW - Structure-Activity Relationship AB - Structural genomics projects aim to solve the experimental structures of all possible protein folds. Such projects entail a conceptual shift from traditional structural biology in which structural information is obtained on known proteins to one in which the structure of a protein is determined first and the function assigned only later. Whereas the goal of converting protein structure into function can be accomplished by traditional sequence motif-based approaches, recent studies have shown that assignment of a protein's biochemical function can also be achieved by scanning its structure for a match to the geometry and chemical identity of a known active site. Importantly, this approach can use low-resolution structures provided by contemporary structure prediction methods. When applied to genomes, structural information (either experimental or predicted) is likely to play an important role in high-throughput function assignment. VL - 18 UR - http://www.ncbi.nlm.nih.gov/pubmed/10700142 ER - TY - JOUR T1 - Study of hydrogen bonding and solvent polarity effects on the nitrogen NMR shieldings of N,N‐dimethylacetamidine JF - Magnetic Resonance in Chemistry Y1 - 2000 A1 - Michal Witanowski A1 - Wanda Sicinska A1 - Zenobia Biedrzycka A1 - Graham A. Webb AB - Solvent effects on the nitrogen shieldings of N,N-dimethylacetamidine (1) were found to be extremely large for the imino group (about 120 ppm) and for the amino moiety (about 50 ppm). A detailed analysis of the solvent-induced variations revealed contributions from three large interactions. These are due to solvent polarity, hydrogen bonding from solute to solvent, via the NH moiety of the solute, and from solvent to solute, involving the nitrogen lone pairs of the solute. For the imino moiety, large shielding effects are observed due to solvent polarity and solvent-to-solute hydrogen bonding, whereas solute-to solvent hydrogen bonding leads to a large decrease in nitrogen shielding. For the NMe2 group, the changes are of opposite sign and smaller in magnitude. Ab initio CHF-GIAO magnetic shielding calculations employing a 6–31++G** basis set and geometries optimized using the same basis set are reported for 1 and some related molecules. The experimental range of nitrogen shielding considered is about 270 ppm and shows an excellent linear correlation with the calculated results. The least-squares standard deviation amounts to only 1.7% of the observed shielding range. The effects on the nitrogen shielding of 1 caused by full protonation are accurately reproduced within this correlation. Copyright © 2000 John Wiley & Sons, Ltd. VL - 38 UR - http://dx.doi.org/10.1002/(SICI)1097-458X(200003)38:3<177::AID-MRC621>3.0.CO;2-I ER - TY - JOUR T1 - Three-dimensional modeling of and ligand docking to vitamin D receptor ligand binding domain JF - Proceedings of the National Academy of Sciences Y1 - 2000 A1 - Keiko Yamamoto A1 - Hiroyuki Masuno A1 - Mihwa Choi A1 - Kinichi Nakashima A1 - Tetsuya Taga A1 - Hiroshi Ooizumi A1 - Kazuhiko Umesono A1 - Wanda Sicinska A1 - Janeen VanHooke A1 - Hector F. DeLuca A1 - Sachiko Yamada AB - The ligand binding domain of the human vitamin D receptor (VDR) was modeled based on the crystal structure of the retinoic acid receptor. The ligand binding pocket of our VDR model is spacious at the helix 11 site and confined at the β-turn site. The ligand 1α,25-dihydroxyvitamin D3 was assumed to be anchored in the ligand binding pocket with its side chain heading to helix 11 (site 2) and the A-ring toward the β-turn (site 1). Three residues forming hydrogen bonds with the functionally important 1α- and 25-hydroxyl groups of 1α,25-dihydroxyvitamin D3 were identified and confirmed by mutational analysis: the 1α-hydroxyl group is forming pincer-type hydrogen bonds with S237 and R274 and the 25-hydroxyl group is interacting with H397. Docking potential for various ligands to the VDR model was examined, and the results are in good agreement with our previous three-dimensional structure-function theory. VL - 97 UR - http://www.pnas.org/content/97/4/1467.abstract ER - TY - JOUR T1 - Ab initio folding of proteins using restraints derived from evolutionary information JF - Proteins Y1 - 1999 A1 - Angel. R. Ortiz A1 - Andrzej Koliński A1 - Piotr Rotkiewicz A1 - Bartosz Ilkowski A1 - Jeffrey Skolnick KW - Algorithms KW - Amino Acid Sequence KW - Evolution KW - Models KW - Molecular KW - Molecular Sequence Data KW - Monte Carlo Method KW - Protein Folding KW - Proteins KW - Proteins: chemistry AB - We present our predictions in the ab initio structure prediction category of CASP3. Eleven targets were folded, using a method based on a Monte Carlo search driven by secondary and tertiary restraints derived from multiple sequence alignments. Our results can be qualitatively summarized as follows: The global fold can be considered "correct" for targets 65 and 74, "almost correct" for targets 64, 75, and 77, "half-correct" for target 79, and "wrong" for targets 52, 56, 59, and 63. Target 72 has not yet been solved experimentally. On average, for small helical and alpha/beta proteins (on the order of 110 residues or smaller), the method predicted low resolution structures with a reasonably good prediction of the global topology. Most encouraging is that in some situations, such as with target 75 and, particularly, target 77, the method can predict a substantial portion of a rare or even a novel fold. However, the current method still fails on some beta proteins, proteins over the 110-residue threshold, and sequences in which only a poor multiple sequence alignment can be built. On the other hand, for small proteins, the method gives results of quality at least similar to that of threading, with the advantage of not being restricted to known folds in the protein database. Overall, these results indicate that some progress has been made on the ab initio protein folding problem. Detailed information about our results can be obtained by connecting to http:/(/)www.bioinformatics.danforthcenter.org/+ ++CASP3. VL - Suppl. 3 UR - http://www.ncbi.nlm.nih.gov/pubmed/10526366 ER - TY - CHAP T1 - Application of reduced models to protein structure prediction T2 - Theoretical and Computational Chemistry: Computational Molecular Biology Y1 - 1999 A1 - Jeffrey Skolnick A1 - Andrzej Koliński A1 - Angel. R. Ortiz AB - This chapter describes the state of the art of contemporary approaches to protein tertiary structure prediction, and focuses on reduced models. Any successful tertiary structure prediction algorithm must address two intertwined issues: first, it is required to have an energy or fitness function that distinguishes the native conformation from the sea of alternative structures. Second, it must have a conformational search protocol that can find the native conformation among the possible alternative structures. A key issue that is faced when embarking on a program of protein structure prediction is deciding on the level of detail of protein representation. The advantage of a lattice is purely computational. Because the protein is confined to a set of grid points, many geometric and energetic properties can be precalculated in advance. Thus, a well-designed lattice model is about a factor of 10 to 100 times faster than the corresponding continuous space model. JF - Theoretical and Computational Chemistry: Computational Molecular Biology PB - Elsevier CY - Amsterdam VL - 8 UR - http://www.sciencedirect.com/science/article/pii/S1380732399800867 ER - TY - JOUR T1 - Assessing energy functions for flexible docking JF - Journal of Computational Chemistry Y1 - 1999 A1 - Michal Vieth A1 - Jonathan D. Hirst A1 - Andrzej Koliński A1 - Charles L. Brooks III KW - docking KW - dynamics KW - energy functions KW - Molecular KW - scoring functions KW - simulated annealing AB - A good docking algorithm requires an energy function that is selective, in that it clearly differentiates correctly docked structures from misdocked ones, and that is efficient, meaning that a correctly docked structure can be identified quickly. We assess the selectivity and efficiency of a broad spectrum of energy functions, derived from systematic modifications of the CHARMM param19/toph19 energy function. In particular, we examine the effects of the dielectric constant, the solvation model, the scaling of surface charges, reduction of van der Waals repulsion, and nonbonded cutoffs. Based on an assessment of the energy functions for the docking of five different ligand–receptor complexes, we find that selective energy functions include a variety of distance-dependent dielectric models together with truncation of the nonbonded interactions at 8 Å. We evaluate the docking efficiency, the mean number of docked structures per unit of time, of the more selective energy functions, using a simulated annealing molecular dynamics protocol. The largest improvements in efficiency come from a reduction of van der Waals repulsion and a reduction of surface charges. We note that the most selective potential is quite inefficient, although a hierarchical approach can be employed to take advantage of both selective and efficient energy functions. VL - 19 UR - http://onlinelibrary.wiley.com/doi/10.1002/(SICI)1096-987X(19981115)19:14%3C1612::AID-JCC7%3E3.0.CO;2-M/abstract IS - 14 ER - TY - CHAP T1 - Contact map T2 - Encyclopedia of Molecular Biology Y1 - 1999 A1 - Andrzej Koliński A1 - Adam Godzik A1 - Jeffrey Skolnick JF - Encyclopedia of Molecular Biology PB - John Wiley & Sons CY - New York ER - TY - JOUR T1 - Correlation between knowledge-based and detailed atomic potentials: application to the unfolding of the GCN4 leucine zipper JF - Proteins Y1 - 1999 A1 - Debasisa Mohanty A1 - Brian N. Dominy A1 - Andrzej Koliński A1 - Charles L. Brooks III A1 - Jeffrey Skolnick KW - DNA-Binding Proteins KW - Fungal Proteins KW - Fungal Proteins: chemistry KW - Leucine Zippers KW - Protein Denaturation KW - Protein Kinases KW - Protein Kinases: chemistry KW - Saccharomyces cerevisiae Proteins KW - Thermodynamics AB - The relationship between the unfolding pseudo free energies of reduced and detailed atomic models of the GCN4 leucine zipper is examined. Starting from the native crystal structure, a large number of conformations ranging from folded to unfolded were generated by all-atom molecular dynamics unfolding simulations in an aqueous environment at elevated temperatures. For the detailed atomic model, the pseudo free energies are obtained by combining the CHARMM all-atom potential with a solvation component from the generalized Born, surface accessibility, GB/SA, model. Reduced model energies were evaluated using a knowledge-based potential. Both energies are highly correlated. In addition, both show a good correlation with the root mean square deviation, RMSD, of the backbone from native. These results suggest that knowledge-based potentials are capable of describing at least some of the properties of the folded as well as the unfolded states of proteins, even though they are derived from a database of native protein structures. Since only conformations generated from an unfolding simulation are used, we cannot assess whether these potentials can discriminate the native conformation from the manifold of alternative, low-energy misfolded states. Nevertheless, these results also have significant implications for the development of a methodology for multiscale modeling of proteins that combines reduced and detailed atomic models. VL - 35 UR - http://www.ncbi.nlm.nih.gov/pubmed/10382672 ER - TY - JOUR T1 - De novo predictions of the quaternary structure of leucine zippers and other coiled coils JF - International Journal of Quantum Chemistry Y1 - 1999 A1 - Jeffrey Skolnick A1 - Andrzej Koliński A1 - Debasisa Mohanty KW - coiled coil KW - lattice protein models KW - Leucine Zippers KW - protein structure prediction KW - quaternary structure prediction AB - Coiled coils possess a quaternary structure comprised of the side-by-side arrangement of a-helices. Due their inherent structural simplicity, they are ideal model systems for both theoretical and experimental studies. Among the coiled coils are the leucine zippers, which play an important role in the activation of DNA transcription. In contrast to the large amount of available experimental data, an overview of which is presented, there are very few theoretical studies. To address this need, the status of existing theoretical approaches to predict coiled coil quaternary structure is described. Furthermore, to treat the conformational equilibria inherent in these systems, an extension of entropy sampling Monte Carlo simulations is developed that can treat multimers. Here, the approach is applied to GCN4 leucine zippers in the context of a reduced protein model. Not only is the native conformation successfully predicted, but the model also reproduces the experimentally observed helix content in the denatured state and the observed two-state thermodynamic behavior. Such two-state behavior arises from the dissociation of highly helical dimeric chains to form monomers of low, isolated chain helix content. VL - 75 UR - http://cssb.biology.gatech.edu/skolnick/publications/pdffiles/183.pdf ER - TY - JOUR T1 - De novo simulations of the folding thermodynamics of the GCN4 leucine zipper JF - Biophysical Journal Y1 - 1999 A1 - Debasisa Mohanty A1 - Andrzej Koliński A1 - Jeffrey Skolnick KW - Computer Simulation KW - Dimerization KW - DNA-Binding Proteins KW - Fungal Proteins KW - Fungal Proteins: chemistry KW - Leucine Zippers KW - Monte Carlo Method KW - Protein Conformation KW - Protein Denaturation KW - Protein Folding KW - Protein Kinases KW - Protein Kinases: chemistry KW - Protein Structure KW - Saccharomyces cerevisiae Proteins KW - Secondary KW - Temperature KW - Thermodynamics AB - Entropy Sampling Monte Carlo (ESMC) simulations were carried out to study the thermodynamics of the folding transition in the GCN4 leucine zipper (GCN4-lz) in the context of a reduced model. Using the calculated partition functions for the monomer and dimer, and taking into account the equilibrium between the monomer and dimer, the average helix content of the GCN4-lz was computed over a range of temperatures and chain concentrations. The predicted helix contents for the native and denatured states of GCN4-lz agree with the experimental values. Similar to experimental results, our helix content versus temperature curves show a small linear decline in helix content with an increase in temperature in the native region. This is followed by a sharp transition to the denatured state. van't Hoff analysis of the helix content versus temperature curves indicates that the folding transition can be described using a two-state model. This indicates that knowledge-based potentials can be used to describe the properties of the folded and unfolded states of proteins. VL - 77 SN - 6197848821 UR - http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1300312&tool=pmcentrez&rendertype=abstract ER - TY - JOUR T1 - Dynamics and thermodynamics of beta-hairpin assembly: insights from various simulation techniques JF - Biophysical Journal Y1 - 1999 A1 - Andrzej Koliński A1 - Bartosz Ilkowski A1 - Jeffrey Skolnick KW - Amino Acid Sequence KW - Animals KW - Biophysical Phenomena KW - Biophysics KW - Models KW - Molecular KW - Molecular Sequence Data KW - Monte Carlo Method KW - Nerve Tissue Proteins KW - Nerve Tissue Proteins: chemistry KW - Protein Conformation KW - Protein Folding KW - Protein Structure KW - Proteins KW - Proteins: chemistry KW - Secondary KW - Thermodynamics AB - Small peptides that might have some features of globular proteins can provide important insights into the protein folding problem. Two simulation methods, Monte Carlo Dynamics (MCD), based on the Metropolis sampling scheme, and Entropy Sampling Monte Carlo (ESMC), were applied in a study of a high-resolution lattice model of the C-terminal fragment of the B1 domain of protein G. The results provide a detailed description of folding dynamics and thermodynamics and agree with recent experimental findings (. Nature. 390:196-197). In particular, it was found that the folding is cooperative and has features of an all-or-none transition. Hairpin assembly is usually initiated by turn formation; however, hydrophobic collapse, followed by the system rearrangement, was also observed. The denatured state exhibits a substantial amount of fluctuating helical conformations, despite the strong beta-type secondary structure propensities encoded in the sequence. VL - 77 UR - http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1300567&tool=pmcentrez&rendertype=abstract ER - TY - JOUR T1 - Hydrogen-bond and solvent polarity effects on the nitrogen NMR shielding of urea systems JF - Journal of Molecular Structure Y1 - 1999 A1 - Michal Witanowski A1 - Wanda Sicinska A1 - Zenobia Biedrzycka A1 - Graham A. Webb KW - Hydrogen-bonding KW - Nitrogen Shieldings KW - Solvent polarity effects KW - Tetramethylurea KW - Urea AB - High precision 14N NMR measurements of the nitrogen shieldings of tetramethylurea, 1, and urea, 2, are reported for dilute solutions in a set of solvents which represent a wide spectrum of properties from the point of view of hydrogen-bonding and solvent polarity/polarisability. It is shown that solvent induced nitrogen shielding changes are appreciable and can be attributed to solute-to-solvent, solvent-to-solute hydrogen-bonding and solvent polarity effects. All of these interactions produce deshielding of the nitrogen nuclei of 1 and 2. This is in accord with an enhanced delocalisation of the nitrogen lone-pair electrons into the π systems of 1 and 2 due to the solute–solvent interactions. GIAO-CHF ab Initio molecular orbital calculations, using a 6-31++G** basis set, are reported for the nitrogen shieldings of the isolated molecules 1 and 2. These reproduce quite well the position of the urea nitrogen resonance obtained in a dilute solution in cyclohexane, with respect to some model compounds which include amino and amido moieties. VL - 476 UR - http://www.sciencedirect.com/science/article/pii/S0022286098005407 ER - TY - JOUR T1 - A method for the improvement of threading-based protein models JF - Proteins Y1 - 1999 A1 - Andrzej Koliński A1 - Piotr Rotkiewicz A1 - Bartosz Ilkowski A1 - Jeffrey Skolnick KW - Amino Acid Sequence KW - Computer Simulation KW - Evaluation Studies as Topic KW - Methods KW - Models KW - Molecular KW - Molecular Sequence Data KW - Protein Conformation KW - Protein Structure KW - Proteins KW - Proteins: chemistry KW - Secondary KW - Sequence Alignment KW - Software Design AB - A new method for the homology-based modeling of protein three-dimensional structures is proposed and evaluated. The alignment of a query sequence to a structural template produced by threading algorithms usually produces low-resolution molecular models. The proposed method attempts to improve these models. In the first stage, a high-coordination lattice approximation of the query protein fold is built by suitable tracking of the incomplete alignment of the structural template and connection of the alignment gaps. These initial lattice folds are very similar to the structures resulting from standard molecular modeling protocols. Then, a Monte Carlo simulated annealing procedure is used to refine the initial structure. The process is controlled by the model's internal force field and a set of loosely defined restraints that keep the lattice chain in the vicinity of the template conformation. The internal force field consists of several knowledge-based statistical potentials that are enhanced by a proper analysis of multiple sequence alignments. The template restraints are implemented such that the model chain can slide along the template structure or even ignore a substantial fraction of the initial alignment. The resulting lattice models are, in most cases, closer (sometimes much closer) to the target structure than the initial threading-based models. All atom models could easily be built from the lattice chains. The method is illustrated on 12 examples of target/template pairs whose initial threading alignments are of varying quality. Possible applications of the proposed method for use in protein function annotation are briefly discussed. VL - 37 UR - http://www.ncbi.nlm.nih.gov/pubmed/10651275 ER - TY - CHAP T1 - Monte Carlo approaches to the protein folding problem T2 - Advances in Chemical Physics: Monte Carlo Methods in Chemical Physics Y1 - 1999 A1 - Jeffrey Skolnick A1 - Andrzej Koliński KW - cooperativity KW - dynamic Monte Carlo dynamics KW - Peptides KW - protein dynamics KW - protein-folding dynamics JF - Advances in Chemical Physics: Monte Carlo Methods in Chemical Physics PB - John Wiley & Sons CY - Hoboken, NJ, USA VL - 105 SN - 9780471196303 UR - http://cssb.biology.gatech.edu/skolnick/publications/pdffiles/159.pdf ER - TY - Generic T1 - The role of computational biology in the genomics revolution T2 - Impact of Advances in Computing and Communications Technologies on Chemical Sciences and Technology, Proceedings of the National Research Council Y1 - 1999 A1 - Jeffrey Skolnick A1 - Jacquelyn S. Fetrow A1 - Angel. R. Ortiz A1 - Andrzej Koliński JF - Impact of Advances in Computing and Communications Technologies on Chemical Sciences and Technology, Proceedings of the National Research Council PB - National Academy Press CY - Washington, D.C. VL - pp UR - http://www.ncbi.nlm.nih.gov/books/NBK44980/ ER - TY - Generic T1 - Application of a high coordination lattice model in protein structure prediction T2 - Proceedings of HRLC Workshop Y1 - 1998 A1 - Andrzej Koliński A1 - Piotr Rotkiewicz A1 - Jeffrey Skolnick JF - Proceedings of HRLC Workshop PB - World Scientific CY - Singapore/London VL - pp UR - http://cssb.biology.gatech.edu/skolnick/publications/pdffiles/175.pdf ER - TY - JOUR T1 - Assembly of protein structure from sparse experimental data: an efficient Monte Carlo model JF - Proteins Y1 - 1998 A1 - Andrzej Koliński A1 - Jeffrey Skolnick KW - Algorithms KW - Computer Simulation KW - Models KW - Molecular KW - Monte Carlo Method KW - Protein Conformation KW - Protein Folding KW - Protein Structure KW - Secondary KW - Tertiary AB - A new, efficient method for the assembly of protein tertiary structure from known, loosely encoded secondary structure restraints and sparse information about exact side chain contacts is proposed and evaluated. The method is based on a new, very simple method for the reduced modeling of protein structure and dynamics, where the protein is described as a lattice chain connecting side chain centers of mass rather than Calphas. The model has implicit built-in multibody correlations that simulate short- and long-range packing preferences, hydrogen bonding cooperativity and a mean force potential describing hydrophobic interactions. Due to the simplicity of the protein representation and definition of the model force field, the Monte Carlo algorithm is at least an order of magnitude faster than previously published Monte Carlo algorithms for structure assembly. In contrast to existing algorithms, the new method requires a smaller number of tertiary restraints for successful fold assembly; on average, one for every seven residues as compared to one for every four residues. For example, for smaller proteins such as the B domain of protein G, the resulting structures have a coordinate root mean square deviation (cRMSD), which is about 3 A from the experimental structure; for myoglobin, structures whose backbone cRMSD is 4.3 A are produced, and for a 247-residue TIM barrel, the cRMSD of the resulting folds is about 6 A. As would be expected, increasing the number of tertiary restraints improves the accuracy of the assembled structures. The reliability and robustness of the new method should enable its routine application in model building protocols based on various (very sparse) experimentally derived structural restraints. VL - 32 UR - http://www.ncbi.nlm.nih.gov/pubmed/9726417 ER - TY - Generic T1 - Combined multiple sequence reduced protein model approach to predict the tertiary structure of small proteins T2 - Proceedings of the Pacific Symposium on Biocomputing ’98 Y1 - 1998 A1 - Angel. R. Ortiz A1 - Andrzej Koliński A1 - Jeffrey Skolnick AB - By incorporating predicted secondary and tertiary restraints into ab initio folding simulations, low resolution tertiary structures of a test set of 20 nonhomologous proteins have been predicted. These proteins, which represent all secondary structural classes, contain from 37 to 100 residues. Secondary structural restraints are provided by the PHD secondary structure prediction algorithm that incorporates multiple sequence information. Predicted tertiary restraints are obtained from multiple sequence alignments via a two-step process: First, "seed" side chain contacts are identified from a correlated mutation analysis, and then, the seed contacts are "expanded" by an inverse folding algorithm. These predicted restraints are then incorporated into a lattice based, reduced protein model. Depending upon fold complexity, the resulting nativelike topologies exhibit a coordinate root-mean-square deviation, cRMSD, from native between 3.1 and 6.7 A. Overall, this study suggests that the use of restraints derived from multiple sequence alignments combined with a fold assembly algorithm is a promising approach to the prediction of the global topology of small proteins. JF - Proceedings of the Pacific Symposium on Biocomputing ’98 VL - pp UR - http://ub.cbm.uam.es/publications/downloads/pdfs/9697197.pdf ER - TY - JOUR T1 - Computer simulations of de novo designed helical proteins JF - Biophysical Journal Y1 - 1998 A1 - Andrzej Sikorski A1 - Andrzej Koliński A1 - Jeffrey Skolnick KW - Amino Acid Sequence KW - Biophysical Phenomena KW - Biophysics KW - Computer Simulation KW - Dimerization KW - Drug Design KW - Hydrogen Bonding KW - Models KW - Molecular KW - Molecular Sequence Data KW - Monte Carlo Method KW - Protein Conformation KW - Protein Folding KW - Protein Structure KW - Proteins KW - Proteins: chemistry KW - Secondary KW - Thermodynamics AB - In the context of reduced protein models, Monte Carlo simulations of three de novo designed helical proteins (four-member helical bundle) were performed. At low temperatures, for all proteins under consideration, protein-like folds having different topologies were obtained from random starting conformations. These simulations are consistent with experimental evidence indicating that these de novo designed proteins have the features of a molten globule state. The results of Monte Carlo simulations suggest that these molecules adopt four-helix bundle topologies. They also give insight into the possible mechanism of folding and association, which occurs in these simulations by on-site assembly of the helices. The low-temperature conformations of all three sequences have the features of a molten globule state. VL - 75 UR - http://www.ncbi.nlm.nih.gov/pubmed/10651035 ER - TY - JOUR T1 - An efficient Monte Carlo model of protein chains. Modeling the short-range correlations between side group centers of mass JF - The Journal of Physycal Chemistry B Y1 - 1998 A1 - Andrzej Koliński A1 - Lukasz Jaroszewski A1 - Piotr Rotkiewicz A1 - Jeffrey Skolnick AB - A new high-coordination lattice model of polypeptide chains has been designed and tested. The model employs a single united atom representation of amino acid residues. These atoms are centered on protein side groups. Characteristic short-range distance correlations have been built into the model, thereby providing a rather accurate description of proteinlike conformational stiffness. Sequence-specific interaction schemes have been derived from sequence similarity and sequence-structure compatibility criteria. The conformations of the model chain observed in isothermal Monte Carlo simulations reproduce protein secondary structure with high fidelity. Implications for structural studies of protein systems are briefly discussed. VL - 102 UR - http://pubs.acs.org/doi/abs/10.1021/jp973371j IS - 23 ER - TY - JOUR T1 - Fold assembly of small proteins using monte carlo simulations driven by restraints derived from multiple sequence alignments JF - Journal of Molecular Biology Y1 - 1998 A1 - Angel. R. Ortiz A1 - Andrzej Koliński A1 - Jeffrey Skolnick KW - Amino Acid Sequence KW - Chemical KW - Models KW - Molecular Sequence Data KW - Monte Carlo Method KW - Protein Folding KW - Protein Structure KW - Secondary KW - Tertiary AB - The feasibility of predicting the global fold of small proteins by incorporating predicted secondary and tertiary restraints into ab initio folding simulations has been demonstrated on a test set comprised of 20 non-homologous proteins, of which one was a blind prediction of target 42 in the recent CASP2 contest. These proteins contain from 37 to 100 residues and represent all secondary structural classes and a representative variety of global topologies. Secondary structure restraints are provided by the PHD secondary structure prediction algorithm that incorporates multiple sequence information. Predicted tertiary restraints are derived from multiple sequence alignments via a two-step process. First, seed side-chain contacts are identified from correlated mutation analysis, and then a threading-based algorithm is used to expand the number of these seed contacts. A lattice-based reduced protein model and a folding algorithm designed to incorporate these predicted restraints is described. Depending upon fold complexity, it is possible to assemble native-like topologies whose coordinate root-mean-square deviation from native is between 3.0 A and 6.5 A. The requisite level of accuracy in side-chain contact map prediction can be roughly 25% on average, provided that about 60% of the contact predictions are correct within +/-1 residue and 95% of the predictions are correct within +/-4 residues. Precision in tertiary contact prediction is more critical than absolute accuracy. Furthermore, only a subset of the tertiary contacts, on the order of 25% of the total, is sufficient for successful topology assembly. Overall, this study suggests that the use of restraints derived from multiple sequence alignments combined with a fold assembly algorithm holds considerable promise for the prediction of the global topology of small proteins. VL - 277 UR - http://www.ncbi.nlm.nih.gov/pubmed/9514747 ER - TY - JOUR T1 - Monte Carlo studies of the thermodynamics and kinetics of reduced protein models: Application to small helical, β, and α / β proteins JF - Journal of Chemical Physics Y1 - 1998 A1 - Andrzej Koliński A1 - Wojciech Galazka A1 - Jeffrey Skolnick AB - Employing a high coordination lattice model and conformational sampling based on dynamic and entropy sampling Monte Carlo protocols, computer experiments were performed on three small globular proteins, each representing one of the three secondary structure classes. The goal was to explore the thermodynamic character of the conformational transition and possible mechanisms of topology assembly. Depending on the stability of isolated elements of secondary structure, topology assembly can proceed by various mechanisms. For the three-helix bundle, protein A, which exhibits substantial helix content in the denatured state, a diffusion–collision mechanism of topology assembly dominates, and here, the conformational transition is predicted to be continuous. In contrast, a model β protein, which possesses little intrinsic denatured state secondary structure, exhibits a sequential "on-site" assembly mechanism and a conformational transition that is well described by a two-state model. Augmenting the cooperativity of tertiary interactions led to a slight shift toward the diffusion–collision model of assembly. Finally, simulations of the folding of the α / β protein G, while only partially successful, suggest that the C-terminal β hairpin should be an early folding conformation and that the N-terminal β hairpin is considerably less stable in isolation. Implications of these results for our general understanding of the process of protein folding and their utility for de novo structure prediction are briefly discussed. VL - 108 UR - http://smartech.gatech.edu/handle/1853/26988 ER - TY - JOUR T1 - Nativelike topology assembly of small proteins using predicted restraints in Monte Carlo folding simulations JF - Proceedings of the National Academy of Sciences of the United States of America Y1 - 1998 A1 - Angel. R. Ortiz A1 - Andrzej Koliński A1 - Jeffrey Skolnick KW - Algorithms KW - Models KW - Molecular KW - Monte Carlo Method KW - Protein Folding KW - Protein Structure KW - Secondary KW - Sequence Alignment KW - Software KW - Tertiary AB - By incorporating predicted secondary and tertiary restraints derived from multiple sequence alignments into ab initio folding simulations, it has been possible to assemble native-like tertiary structures for a test set of 19 nonhomologous proteins ranging from 29 to 100 residues in length and representing all secondary structural classes. Secondary structural restraints are provided by the PHD secondary structure prediction algorithm that incorporates multiple sequence information. Multiple sequence alignments also provide predicted tertiary restraints via a two-step process: First, seed side chain contacts are selected from a correlated mutation analysis, and then an inverse folding algorithm expands these seed contacts. The predicted secondary and tertiary restraints are incorporated into a lattice-based, reduced protein model for structure assembly and refinement. The resulting native-like topologies exhibit a coordinate root-mean-square deviation from native for the whole chain between 3.1 and 6.7 A, with values ranging from 2.6 to 4.1 A over approximately 80% of the structure. Overall, this study suggests that the use of restraints derived from multiple sequence alignments combined with a fold assembly algorithm is a promising approach to the prediction of the global topology of small proteins. VL - 95 UR - http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=18658&tool=pmcentrez&rendertype=abstract ER - TY - JOUR T1 - Reduced protein models and their application to the protein folding problem JF - Journal of Biomolecular Structure and Dynamics Y1 - 1998 A1 - Jeffrey Skolnick A1 - Andrzej Koliński A1 - Angel. R. Ortiz AB - One of the most important unsolved problems of computational biology is prediction of the three-dimensional structure of a protein from its amino acid sequence. In practice, the solution to the protein folding problem demands that two interrelated problems be simultaneously addressed. Potentials that recognize the native state from the myriad of misfolded conformations are required, and the multiple minima conformational search problem must be solved. A means of partly surmounting both problems is to use reduced protein models and knowledge-based potentials. Such models have been employed to elucidate a number of general features of protein folding, including the nature of the energy landscape, the factors responsible for the uniqueness of the native state and the origin of the two-state thermodynamic behavior of globular proteins. Reduced models have also been used to predict protein tertiary and quaternary structure. When combined with a limited amount of experimental information about secondary and tertiary structure, molecules of substantial complexity can be assembled. If predicted secondary structure and tertiary restraints are employed, low resolution models of single domain proteins can be successfully predicted. Thus, simplified protein models have played an important role in furthering the understanding of the physical properties of proteins. VL - 16 UR - http://www.tandfonline.com/doi/abs/10.1080/07391102.1998.10508255 ER - TY - JOUR T1 - A Study of Solvent Polarity and Hydrogen Bonding Effects on the Nitrogen NMR Shielding of Isomeric Tetrazoles andab InitioCalculation of the Nitrogen Shielding of Azole Systems JF - Journal of Magnetic Resonance Y1 - 1998 A1 - Michal Witanowski A1 - Zenobia Biedrzycka A1 - Wanda Sicinska A1 - Zbigniew Grabowski KW - azoles KW - calculations KW - diazoles KW - nitrogen chemical shifts KW - nitrogen NMR KW - Nitrogen Shieldings KW - Solvent effects KW - tetrazoles KW - triazoles AB - High-precision nitrogen NMR shieldings, bulk susceptibility corrected, are reported for theN-methyl derivatives of the two existing isomeric tetrazoles (I, II) in a variety of solvents which represent a wide range of solvent properties from the point of view of polarity as well as hydrogen bond donor and acceptor strength. The observed range of solvent-induced nitrogen shielding variations of I and İI\} is significant for the pyrrole-type nitrogens (N-Me), up to 9 ppm, and even more so for pyridine-type nitrogen atoms, where it can attain a value of 20 ppm. There is a clear distinction between the two types of nitrogen atoms in that the former exhibit a deshielding effect with increasing polarity of the medium while the latter experience an increase in the magnetic shielding of their nuclei. The latter effect is significantly augmented by solvent-to-solute hydrogen-bond formation where the pyridine-type nitrogens are involved directly. It is also quite diversified throughout the pyridine-type nitrogen atoms and seems to constitute a measure of relative basicity with respect to hydrogen-bond formation of the nitrogens concerned. This basicity seems to parallel that with respect to a full transfer of a proton, as can be reckoned fromab initiocalculations of the relevant protonation energies reported in the present study. The experimental data for the tetrazoles in cyclohexane solutions are combined with those obtained in our earlier extensive studies on azole, diazole, and triazole ring systems, for a comparison withab initiocalculations of the nitrogen shieldings concerned. The latter were carried out using the coupled Hartree–Fock/GIAO/6−31++G** approach and geometry optimizations employing the same basis set; they show a good linear correlation with the experimental data and reproduce not only major changes but also most of the subtle variations in the experimental nitrogen shieldings of the azole systems as a whole. VL - 131 UR - http://www.sciencedirect.com/science/article/pii/S1090780797913252 ER - TY - JOUR T1 - Tertiary structure prediction of the KIX domain of CBP using Monte Carlo simulations driven by restraints derived from multiple sequence alignments JF - Proteins Y1 - 1998 A1 - Angel. R. Ortiz A1 - Andrzej Koliński A1 - Jeffrey Skolnick KW - Algorithms KW - Amino Acid Sequence KW - CREB-Binding Protein KW - Databases as Topic KW - Models KW - Molecular KW - Molecular Sequence Data KW - Monte Carlo Method KW - Mutation KW - Mutation: genetics KW - Nuclear Proteins KW - Nuclear Proteins: chemistry KW - Protein Folding KW - Protein Structure KW - Secondary KW - Sequence Alignment KW - Tertiary KW - Trans-Activators KW - Transcription Factors KW - Transcription Factors: chemistry AB - Using a recently developed protein folding algorithm, a prediction of the tertiary structure of the KIX domain of the CREB binding protein is described. The method incorporates predicted secondary and tertiary restraints derived from multiple sequence alignments in a reduced protein model whose conformational space is explored by Monte Carlo dynamics. Secondary structure restraints are provided by the PHD secondary structure prediction algorithm that was modified for the presence of predicted U-turns, i.e., regions where the chain reverses global direction. Tertiary restraints are obtained via a two-step process: First, seed side-chain contacts are identified from a correlated mutation analysis, and then, a threading-based algorithm expands the number of these seed contacts. Blind predictions indicate that the KIX domain is a putative three-helix bundle, although the chirality of the bundle could not be uniquely determined. The expected root-mean-square deviation for the correct chirality of the KIX domain is between 5.0 and 6.2 A. This is to be compared with the estimate of 12.9 A that would be expected by a random prediction, using the model of F. Cohen and M. Sternberg (J. Mol. Biol. 138:321-333, 1980). VL - 30 UR - http://www.ncbi.nlm.nih.gov/pubmed/9517544 ER - TY - JOUR T1 - Algorithm for rapid reconstruction of protein backbone from alpha carbon coordinates JF - Journal of Computational Chemistry Y1 - 1997 A1 - Mariusz Milik A1 - Andrzej Koliński A1 - Jeffrey Skolnick AB - A method for generating a full backbone protein structure from the coordinates of α-carbons, is presented. The method extracts information from known protein structures to generate statistical positions for the reconstructed atoms. Tests on a set of proteins structures show the algorithm to be of comparable accuracy to existing procedures. However, the basic advantage of the presented method is its simplicity and speed. In a test run, the present program is shown to be much faster than existing database searching algorithms, and reconstructs about 8000 residues per second. Thus, it may be included as an independent procedure in protein folding algorithms to rapidly generate approximate coordinates of backbone atoms. VL - 18 UR - http://doi.wiley.com/10.1002/(SICI)1096-987X(19970115)18:1<80::AID-JCC8>3.0.CO;2-W ER - TY - JOUR T1 - Collapse transitions in protein-like lattice polymers: The effect of sequence patterns JF - Biopolymers Y1 - 1997 A1 - Andrzej Koliński A1 - Pawel Madziar KW - collapse transition KW - Lattice proteins KW - Monte Carlo Method KW - protein models KW - sequence patterns AB - The collapse transition of lattice protein-like heteropolymers has been studied by means of the Monte Carlo method. The protein model has been reduced to the α-carbon trace restricted to a high coordination lattice. The sequences of model heteropolymers contain two types of mers: hydrophobic/nonpolar (H) and hydrophilic/polar (P). Interactions of HH and PP pairs were assumed to be negative (weaker attractions of PP pairs) while the contact energy for HP pairs was equal to zero. All sequence-specific short-range interactions have been neglected in the present studies. It has been found that homopolymeric chains undergo a smooth collapse transition to a dense globular state. The globule lacks any signatures of local ordering that could be interpreted as a model of protein secondary structure. Hetero-polymers with the sequences of hydrophilic and hydrophobic residues characteristic for α- and β-type proteins undergo a somewhat sharper (though continuous) collapse transition to a dense globular state with elements of local ordering controlled by the sequence. The helical pattern induces more secondary structure than the β-type pattern. For all examined sequences the level of local ordering was lower than the average secondary structure content of globular proteins. The results are compared with other theoretical work and with known experimental facts. The implications for the reduced modeling of protein systems are briefly discussed. © 1997 John Wiley & Sons, Inc. Biopoly 42: 537–548, 1997 VL - 42 IS - 5 ER - TY - JOUR T1 - Derivation and testing of pair potentials for protein folding. When is the quasichemical approximation correct? JF - Protein Science Y1 - 1997 A1 - Jeffrey Skolnick A1 - Lukasz Jaroszewski A1 - Andrzej Koliński A1 - Adam Godzik KW - empirical parameter sets KW - inverse protein folding KW - protein structural database KW - protein threading KW - quasichemical approximation AB - Many existing derivations of knowledge-based statistical pair potentials invoke the quasichemical approximation to estimate the expected side-chain contact frequency if there were no amino acid pair-specific interactions. At first glance, the quasichemical approximation that treats the residues in a protein as being disconnected and expresses the side-chain contact probability as being proportional to the product of the mole fractions of the pair of residues would appear to be rather severe. To investigate the validity of this approximation, we introduce two new reference states in which no specific pair interactions between amino acids are allowed, but in which the connectivity of the protein chain is retained. The first estimates the expected number of side-chain contracts by treating the protein as a Gaussian random coil polymer. The second, more realistic reference state includes the effects of chain connectivity, secondary structure, and chain compactness by estimating the expected side-chain contrast probability by placing the sequence of interest in each member of a library of structures of comparable compactness to the native conformation. The side-chain contact maps are not allowed to readjust to the sequence of interest, i.e., the side chains cannot repack. This situation would hold rigorously if all amino acids were the same size. Both reference states effectively permit the factorization of the side-chain contact probability into sequence-dependent and structure-dependent terms. Then, because the sequence distribution of amino acids in proteins is random, the quasichemical approximation to each of these reference states is shown to be excellent. Thus, the range of validity of the quasichemical approximation is determined by the magnitude of the side-chain repacking term, which is, at present, unknown. Finally, the performance of these two sets of pair interaction potentials as well as side-chain contact fraction-based interaction scales is assessed by inverse folding tests both without and with allowing for gaps. VL - 6 UR - http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2143667&tool=pmcentrez&rendertype=abstract ER - TY - JOUR T1 - Determinants of secondary structure of polypeptide chains: Interplay between short range and burial interactions JF - Journal of Chemical Physics Y1 - 1997 A1 - Andrzej Koliński A1 - Jeffrey Skolnick AB - The effect of tertiary interactions on the observed secondary structure found in the native conformation of globular proteins was examined in the context of a reduced protein model. Short-range interactions are controlled by knowledge based statistical potentials that reflect local conformational regularities seen in a database of three-dimensional protein structures. Long-range interactions are approximated by mean field, single residue based, centrosymmetric hydrophobic burial potentials. Even when pairwise specific long-range interactions are ignored, the inclusion of such burial preferences noticeably modifies the equilibrium chain conformations, and the observed secondary structure is closer to that seen in the folded state. For a test set of 10 proteins (belonging to various structural classes), the accuracy of secondary structure prediction is about 66% and increases by 9% with respect to a related model based on short-range interactions alone [Kolinski et al., J. Chem. Phys. 103, 4312 (1995)]. The increased accuracy is due to the interplay between the short-range conformational propensities and the burial and compactness requirements built into the present model. While the absolute level of accuracy assessed on a per residue basis is comparable to more standard techniques, in contrast to these approaches, the conformation of the chain now has a better defined geometric context. For example, the assumed spherical domain protein model that simulates the segregation of residues between the hydrophobic core and the hydrophilic surface allows for the prediction of surface loops/turns where the polypeptide chain changes its direction. The implications of having such self-consistent secondary structure predictions for the prediction of protein tertiary structure are briefly discussed. VL - 107 UR - http://smartech.gatech.edu/handle/1853/27033 ER - TY - JOUR T1 - High coordination lattice models of protein structure, dynamics and thermodynamics JF - Acta Biochim Polonica Y1 - 1997 A1 - Andrzej Koliński A1 - Jeffrey Skolnick AB - A high coordination lattice discretization of protein conformational space is described. The model allows discrete representation of polypeptide chains of globular proteins and small macromolecular assemblies with an accuracy comparable to the accuracy of crystallographic structures. Knowledge based force field, that consists of sequence specific short range interactions, cooperative model of hydrogen bond network and tertiary one body, two body and multibody interactions, is outlined and discussed. A model of stochastic dynamics for these protein models is also described. The proposed method enables moderate resolution tertiary structure prediction of simple and small globular proteins. Its applicability in structure prediction increases significantly when evolutionary information is exploited or/and when sparse experimental data are available. The model responds correctly to sequence mutations and could be used at early stages of a computer aided protein design and protein redesign. Computational speed, associated with the discrete structure of the model, enables studies of the long time dynamics of polypeptides and proteins and quite detailed theoretical studies of thermodynamics of nontrivial protein models. VL - 44 UR - http://www.actabp.pl/pdf/3\_1997/389.pdf IS - 3 ER - TY - JOUR T1 - Hydrogen Bonding and Solvent Polarity Effects on the Nitrogen NMR Shielding of 1,2,4,5-Tetrazine JF - Journal of Magnetic Resonance Y1 - 1997 A1 - Michal Witanowski A1 - Zenobia Biedrzycka A1 - Wanda Sicinska A1 - Zbigniew Grabowski A1 - Graham A. Webb KW - Solvent polarity effects AB - Results of the first extensive investigation of the nitrogen shielding of 1,2,4,5-tetrazine (I) are reported. Due attention is paid to solvent-induced nitrogen-shielding variations by a variety of solvents. A comparison is made with comparable, earlier, results for the other azine systems. The observed range of solvent-induced nitrogen-shielding variations ofIis modest but significant, about 10 ppm. The major factor producing this variation is that due to solvent polarity effects, which is supported by the results of some shielding calculations based upon the Solvaton model. A smaller, but significant, contribution is produced by solvent-to-solute hydrogen bonding effects. This correlates well with the low nitrogen basicity ofIas indicated by publishedab initiomolecular orbital calculations of gas-phase protonation energies. There is found a general correlation between nitrogen basicity with respect to hydrogen bonding and that with respect to protonation. GIAO/CHF nitrogen-shielding calculations are reported for all of the existing monocyclic heteroaromatic azine systems includingIusing a 6-31++G** basis set. These appear to indicate that the inclusion of electron-correlation effects, reported for the \{SOLO\} method, does not result in a dramatic improvement in the calculated nitrogen shieldings. VL - 124 UR - http://www.sciencedirect.com/science/article/pii/S1090780796910071 ER - TY - JOUR T1 - Improved method for prediction of protein backbone U-turn positions and major secondary structural elements between U-turns JF - Proteins Y1 - 1997 A1 - Wei-Ping Hu A1 - Andrzej Koliński A1 - Jeffrey Skolnick KW - Amino Acid KW - Amino Acid Sequence KW - Amino Acids KW - Amino Acids: chemistry KW - Data Interpretation KW - Models KW - Molecular KW - Molecular Sequence Data KW - Protein Structure KW - Proteins KW - Proteins: chemistry KW - Reproducibility of Results KW - Secondary KW - Sequence Alignment KW - Sequence Alignment: methods KW - Sequence Alignment: statistics & numerical data KW - Sequence Homology KW - Statistical AB - A new and more accurate method has been developed for predicting the backbone U-turn positions (where the chain reverses global direction) and the dominant secondary structure elements between U-turns in globular proteins. The current approach uses sequence-specific secondary structure propensities and multiple sequence information. The latter plays an important role in the enhanced success of this approach. Application to two sets (total 108) of small to medium-sized, single-domain proteins indicates that approximately 94% of the U-turn locations are correctly predicted within three residues, as are 88% of dominant secondary structure elements. These results are significantly better than our previous method (Kolinski et al., Proteins 27:290-308, 1997). The current study strongly suggests that the U-turn locations are primarily determined by local interactions. Furthermore, both global length constraints and local interactions contribute significantly to the determination of the secondary structure types between U-turns. Accurate U-turn predictions are crucial for accurate secondary structure predictions in the current method. Protein structure modeling, tertiary structure predictions, and possibly, fold recognition should benefit from the predicted structural data provided by this new method. VL - 29 UR - http://www.ncbi.nlm.nih.gov/pubmed/9408942 ER - TY - Generic T1 - Method for low resolution prediction of small protein tertiary structure T2 - Proceeding of II-nd Pacific Symposium on Biocomputing Y1 - 1997 A1 - Angel. R. Ortiz A1 - Wei-Ping Hu A1 - Andrzej Koliński A1 - Jeffrey Skolnick AB - A new method for the de novo prediction of protein structures at low resolution has been developed. Starting from a multiple sequence alignment, protein secondary structure is predicted, and only those topological elements with high reliability are selected. Then, the multiple sequence alignment and the secondary structure prediction are combined to predict side chain contacts. Such contact map prediction is carried out in two stages. First, an analysis of correlated mutations is carried out to identify pairs of topological elements of secondary structure which are in contact. Then, inverse folding is used to select compatible fragments in contact, thereby enriching the number and identity of predicted side chain contacts. The final outcome of the procedure is a set of noisy secondary and tertiary restraints. These are used as a restrained potential in a Monte Carlo simulation of simplified protein models driven by statistical potentials. Low energy structures are then searched for by using simulated annealing techniques. Implementation of the restraints is carried out so as to take into account of their low resolution. Using this procedure, it has been possible to predict de novo the structure of three very different protein topologies: an alpha/beta protein, the bovine pancreatic trypsin inhibitor (6pti), an alpha-helical protein, calbindin (3icb), and an all beta- protein, the SH3 domain of spectrin (1shg). In all cases, low resolution folds have been obtained with a root mean square deviation (RMSD) of 4.5-5.5 A with respect to the native structure. Some misfolded topologies appear in the simulations, but it is possible to select the native one on energetic grounds. Thus, it is demonstrated that the methodology is general for all protein motifs. Work is in progress in order to test the methodology on a larger set of protein structures. JF - Proceeding of II-nd Pacific Symposium on Biocomputing PB - World Scientific UR - http://helix-web.stanford.edu/psb97/ortiz.pdf ER - TY - JOUR T1 - A method for the prediction of surface "U"-turns and transglobular connections in small proteins JF - Proteins Y1 - 1997 A1 - Andrzej Koliński A1 - Jeffrey Skolnick A1 - Adam Godzik A1 - Wei-Ping Hu KW - Algorithms KW - Amino Acid Sequence KW - Animals KW - Humans KW - Molecular Sequence Data KW - Protein Folding KW - Protein Structure KW - Proteins KW - Proteins: chemistry KW - Secondary AB - A simple method for predicting the location of surface loops/turns that change the overall direction of the chain that is, "U" turns, and assigning the dominant secondary structure of the intervening transglobular blocks in small, single-domain globular proteins has been developed. Since the emphasis of the method is on the prediction of the major topological elements that comprise the global structure of the protein rather than on a detailed local secondary structure description, this approach is complementary to standard secondary structure prediction schemes. Consequently, it may be useful in the early stages of tertiary structure prediction when establishment of the structural class and possible folding topologies is of interest. Application to a set of small proteins of known structure indicates a high level of accuracy. The prediction of the approximate location of the surface turns/loops that are responsible for the change in overall chain direction is correct in more than 95% of the cases. The accuracy for the dominant secondary structure assignment for the linear blocks between such surface turns/loops is in the range of 82%. VL - 27 UR - http://www.ncbi.nlm.nih.gov/pubmed/9061792 ER - TY - JOUR T1 - MONSSTER: a method for folding globular proteins with a small number of distance restraints JF - Journal of Molecular Biology Y1 - 1997 A1 - Jeffrey Skolnick A1 - Andrzej Koliński A1 - Angel. R. Ortiz KW - Algorithms KW - Aprotinin KW - Aprotinin: chemistry KW - Bacterial Proteins KW - Bacterial Proteins: chemistry KW - Computer Graphics KW - Computer Simulation KW - Flavodoxin KW - Flavodoxin: chemistry KW - Models KW - Molecular KW - Myoglobin KW - Myoglobin: chemistry KW - Plastocyanin KW - Plastocyanin: chemistry KW - Protein Conformation KW - Protein Folding KW - Protein Structure KW - Secondary KW - Tertiary KW - Thioredoxins KW - Thioredoxins: chemistry AB - The MONSSTER (MOdeling of New Structures from Secondary and TEritary Restraints) method for folding of proteins using a small number of long-distance restraints (which can be up to seven times less than the total number of residues) and some knowledge of the secondary structure of regular fragments is described. The method employs a high-coordination lattice representation of the protein chain that incorporates a variety of potentials designed to produce protein-like behaviour. These include statistical preferences for secondary structure, side-chain burial interactions, and a hydrogen-bond potential. Using this algorithm, several globular proteins (1ctf, 2gbl, 2trx, 3fxn, 1mba, 1pcy and 6pti) have been folded to moderate-resolution, native-like compact states. For example, the 68 residue 1ctf molecule having ten loosely defined, long-range restraints was reproducibly obtained with a C alpha-backbone root-mean-square deviation (RMSD) from native of about 4. A. Flavodoxin with 35 restraints has been folded to structures whose average RMSD is 4.28 A. Furthermore, using just 20 restraints, myoglobin, which is a 146 residue helical protein, has been folded to structures whose average RMSD from native is 5.65 A. Plastocyanin with 25 long-range restraints adopts conformations whose average RMSD is 5.44 A. Possible applications of the proposed approach to the refinement of structures from NMR data, homology model-building and the determination of tertiary structure when the secondary structure and a small number of restraints are predicted are briefly discussed. VL - 265 UR - http://www.ncbi.nlm.nih.gov/pubmed/9020984 ER - TY - CHAP T1 - Monte Carlo lattice dynamics and the prediction of protein folds T2 - Computer Simulations of Biomolecular Systems. Theoretical and Experimental Applications Y1 - 1997 A1 - Jeffrey Skolnick A1 - Andrzej Koliński A1 - W. F. van Gunsteren A1 - P.K. Weiner A1 - A. J. Wilkinson JF - Computer Simulations of Biomolecular Systems. Theoretical and Experimental Applications PB - Kluwer Academic Publishers CY - The Netherlands VL - pp UR - http://books.google.com/books?hl=en&lr=&id=B3iDerOPyoUC&oi=fnd&pg=PA395&dq=Monte+Carlo+lattice+dynamics+and+prediction+of+protein+folds&ots=nsZT420e-y&sig=Keu7zbBbOErsB3dYSFtFBfgtCoc http://books.google.com/books?hl=en&lr=&id=B3iDerOPyoUC&oi=fnd&pg=PA395& ER - TY - JOUR T1 - Nitrogen NMR shieldings of 2-amino-5-nitro-6-methylpyridines JF - International Journal of Spectroscopy Y1 - 1997 A1 - B. Palasek A1 - A. Puszko A1 - Zenobia Biedrzycka A1 - Wanda Sicinska A1 - Michal Witanowski VL - 13 ER - TY - JOUR T1 - Solvent and protonation effects on nitrogen NMR shieldings of isoamides (α-aminoethers) JF - Journal of Molecular Structure Y1 - 1997 A1 - Michal Witanowski A1 - Wanda Sicinska A1 - Zenobia Biedrzycka A1 - Graham A. Webb KW - Hydrogen Bonding KW - Isoamide (α-imino ether) KW - Nitrogen NMR shieldings KW - Protonation effects KW - Solvent effects AB - High-precision solvent-induced 14N \{NMR\} shieldings are presented for some isoamides and their N-protonated forms. The results indicate that the major source of solute-solvent interactions, giving rise to nitrogen shielding variations, is solvent-to-solute hydrogen bonding where the lone pair electrons of the imino nitrogen act as the hydrogen-bond acceptor centre. This results in a remarkable shielding increase for the imino nitrogen atom. Another interaction which could be important, when \{NH\} moieties are present, is solute-to-solvent hydrogen bonding where the \{NH\} croup is engaged as a donor. In the present study this effect is found to be a modest one and produces nitrogen deshielding. The influence of non-specific interactions, arising from solvent polarity effects, is rather feeble compared with that for analogous imine systems. The direction and magnitude of this effect is correctly reproduced by molecular orbital calculations incorporating the Solvaton model for non-specific solute-solvent interactions. Protonation effects on the nitrogen shieldings of the isoamides are substantial, producing an increase in shielding of about 80 ppm. This is in accord with that observed for solvent-to-solute hydrogen bonding. VL - 404 UR - http://www.sciencedirect.com/science/article/pii/S0022286096095300 ER - TY - JOUR T1 - Solvent induced variations in nitrogen NMR shieldings of some oxime systems as a test of the Solvaton model of non-specific molecular interactions JF - J. Chem. Soc.{,} Perkin Trans. 2 Y1 - 1997 A1 - Michal Witanowski A1 - Zenobia Biedrzycka A1 - Wanda Sicinska A1 - Graham A. Webb AB - High precision N NMR measurements are reported for three oxime systems in a variety of solvents. Both hydrogen bonding and solvent polarity effects are found to make significant contributions to the observed range of nitrogen shieldings. For a non-conjugated oxime moiety the solvent induced nitrogen shielding variations are found to be of opposite sign to those found for oximes which have a strongly conjugated carbonyl group. These shielding variations are interpreted in terms of solute-solvent specific and non-specific interactions. The analysis of the shielding data results in the view that{,} in these two cases of carbonyl group conjugation{,} there are opposing directions of electronic charge migration as a function of an increase in solvent polarity. There appears to be a change in the preference of the solute hydrogen bond acceptor site from the oxime to the carbonyl moiety in the case of p-benoquinone mono oxime derivatives. Medium polarity effects on the solute nitrogen shielding are adequately accounted for by INDO/S parametrised molecular orbital calculations of nitrogen shieldings as a function of solvent relative permittivity (I[small micro]) by means of the Solvaton model. This model describes satisfactorily the effects of a change in solvent polarity on the nitrogen shielding of a variety of nitrogen containing solutes. PB - The Royal Society of Chemistry UR - http://dx.doi.org/10.1039/A606216D ER - TY - JOUR T1 - Solvent-Induced Effects on the Nitrogen NMR Shieldings of Some Nitrosobenzene Systems JF - Magnetic Resonance in Chemistry Y1 - 1997 A1 - Michal Witanowski A1 - Zenobia Biedrzycka A1 - Wanda Sicinska A1 - Graham A. Webb KW - 14N KW - calculations KW - Nitroso Compounds KW - NMR KW - Solvent effects AB - High-precision14N NMR measurements of solvent-induced shielding variations are reported for some nitrosobenzene systems. These variations are shown to result from a combination of three major factors, solvent to solute hydrogen bonding where the solute nitrogen lone pair electrons are involved, solvent polarity and interactions between the electron-deficient benzene ring of the nitrosobenzenes and basic centres in the solvent molecules. The last of these three factors produces nitrogen deshielding of the nitroso group, and in the present work this interaction was found to be the largest of its type so far observed. Consequently, this implies that, in nitroso aromatic compounds, the benzene ring shows a remarkable deficit of electronic charge. The former two factors produce an increase in nitroso nitrogen shielding, thus indicating a strong electron-withdrawing effect of the nitroso group which is consistent with previous observations. INDO/S parameterized molecular orbital calculations of solute nitrogen shieldings, incorporating the Solvaton model of non-specific solute–solvent interactions, predict that the nitrogen shielding will increase as the polarity of the medium increases. This is in very good agreement with the observation that the nitroso nitrogen shielding analysis yields a large and positive value for thesterm which describes the influence of solvent polarity/polarizability on the shielding variation as a function of solvent. For the 0.2 M solutions studied at 35°C, a significant amount of the dimeric isodioxy form is only observed foro-nitrosotoluene. © 1997 by John Wiley & Sons, Ltd PB - John Wiley & Sons, Ltd. VL - 35 UR - http://dx.doi.org/10.1002/(SICI)1097-458X(199704)35:4<262::AID-OMR96>3.0.CO;2-5 ER - TY - Generic T1 - An algorithm for prediction of structural elements in small proteins T2 - Proceeding of I-st Pacific Symposium on Biocomputing Y1 - 1996 A1 - Andrzej Koliński A1 - Jeffrey Skolnick A1 - Adam Godzik AB - A method for predicting the location of surface loops/turns and assigning the intervening secondary structure of the transglobular linkers in small, single domain globular proteins has been developed. Application to a set of 10 proteins of known structure indicates a high level of accuracy. The secondary structure assignment in the center of transglobular connections is correct in more than 85% of the cases. A similar error rate is found for loops. Since more global information about the fold is provided, it is complementary to standard secondary structure prediction approaches. Consequently, it may be useful in early stages of tertiary structure prediction when establishment of the structural class and possible folding topologies is of interest. JF - Proceeding of I-st Pacific Symposium on Biocomputing UR - http://helix-web.stanford.edu/psb96/kolinski.pdf ER - TY - JOUR T1 - A detailed 1H and 13C NMR study of a repeating disaccharide of hyaluronan: the effect of sodium and calcium ions JF - Carbohydrate Research Y1 - 1996 A1 - Wanda Sicinska A1 - Laura E. Lerner KW - Cation interactions KW - Conformation KW - Hyaluronan KW - NMR VL - 286 UR - http://www.sciencedirect.com/science/article/pii/0008621596000456 ER - TY - JOUR T1 - A detailed 1H and 13C NMR study of a repeating disaccharide of hyaluronan: the effect of sodium and calcium ions JF - Carbohydrate Research Y1 - 1996 A1 - Wanda Sicinska A1 - Laura E. Lerner VL - 286 ER - TY - JOUR T1 - Does a backwardly read protein sequence have a unique native state? JF - Protein Engineering Y1 - 1996 A1 - Krzysztof A. Olszewski A1 - Andrzej Koliński A1 - Jeffrey Skolnick KW - Amino Acid Sequence KW - Computer Simulation KW - Models KW - Molecular KW - Molecular Sequence Data KW - Monte Carlo Method KW - Protein Conformation KW - Protein Engineering KW - Protein Folding KW - Protein Structure KW - Secondary KW - Staphylococcal Protein A KW - Staphylococcal Protein A: chemistry KW - Tertiary AB - Amino acid sequences of native proteins are generally not palindromic. Nevertheless, the protein molecule obtained as a result of reading the sequence backwards, i.e. a retro-protein, obviously has the same amino acid composition and the same hydrophobicity profile as the native sequence. The important questions which arise in the context of retro-proteins are: does a retro-protein fold to a well defined native-like structure as natural proteins do and, if the answer is positive, does a retro-protein fold to a structure similar to the native conformation of the original protein? In this work, the fold of retro-protein A, originated from the retro-sequence of the B domain of Staphylococcal protein A, was studied. As a result of lattice model simulations, it is conjectured that the retro-protein A also forms a three-helix bundle structure in solution. It is also predicted that the topology of the retro-protein A three-helix bundle is that of the native protein A, rather than that corresponding to the mirror image of native protein A. Secondary structure elements in the retro-protein do not exactly match their counterparts in the original protein structure; however, the amino acid side chain contract pattern of the hydrophobic core is partly conserved. VL - 9 UR - http://www.ncbi.nlm.nih.gov/pubmed/9053902 ER - TY - JOUR T1 - Folding simulations and computer redesign of protein A three-helix bundle motifs JF - Proteins Y1 - 1996 A1 - Krzysztof A. Olszewski A1 - Andrzej Koliński A1 - Jeffrey Skolnick KW - Computer Simulation KW - Monte Carlo Method KW - Mutation KW - Protein Conformation KW - Protein Folding KW - Staphylococcal Protein A KW - Staphylococcal Protein A: chemistry AB - In solution, the B domain of protein A from Staphylococcus aureus (B domain) possesses a three-helix bundle structure. This simple motif has been previously reproduced by Kolinski and Skolnick (Proteins 18: 353-366, 1994) using a reduced representation lattice model of proteins with a statistical interaction scheme. In this paper, an improved version of the potential has been used, and the robustness of this result has been tested by folding from the random state a set of three-helix bundle proteins that are highly homologous to the B domain of protein A. Furthermore, an attempt to redesign the B domain native structure to its topological mirror image fold has been made by multiple mutations of the hydrophobic core and the turn region between helices I and II. A sieve method for scanning a large set of mutations to search for this desired property has been proposed. It has been shown that mutations of native B domain hydrophobic core do not introduce significant changes in the protein motif. Mutations in the turn region were also very conservative; nevertheless, a few mutants acquired the desired topological mirror image motif. A set of all atom models of the most probable mutant was reconstructed from the reduced models and refined using a molecular dynamics algorithm in the presence of water. The packing of all atom structures obtained corroborates the lattice model results. We conclude that the change in the handedness of the turn induced by the mutations, augmented by the repacking of hydrophobic core and the additional burial of the second helix N-cap side chain, are responsible for the predicted preferential adoption of the mirror image structure. VL - 25 UR - http://www.ncbi.nlm.nih.gov/pubmed/8844865 ER - TY - JOUR T1 - A hierarchical approach to the prediction of the quaternary structure of GCN4 and its mutants JF - DIMACS Series in Discrete Mathematics and Theoretical Computer Science Y1 - 1996 A1 - Michal Vieth A1 - Andrzej Koliński A1 - Charles L. Brooks III A1 - Jeffrey Skolnick AB - A hierarchical approach to protein folding is employed to examine the folding pathway and predict the quaternary structure of the GCN4 leucine zipper. Structures comparable in quality to experiment have been predicted. In addition, the equilibrium between dimers, trimers and tetramers of a number of GCN4 mutants has been examined. In five out of eight cases, the simulation results are in accordance with the experimental studies of Harbury, et al. VL - 23 UR - http://smartech.gatech.edu/handle/1853/27922 ER - TY - BOOK T1 - Lattice models of protein folding. Dynamics and thermodynamics T2 - Lattice models of protein folding. Dynamics and thermodynamics, Austin, TX, Chapman & Hall. Y1 - 1996 A1 - Andrzej Koliński A1 - Jeffrey Skolnick JF - Lattice models of protein folding. Dynamics and thermodynamics, Austin, TX, Chapman & Hall. PB - Chapman & Hall. CY - Austin, TX ER - TY - JOUR T1 - Method for predicting the state of association of discretized protein models. Application to leucine zippers. JF - Biochemistry Y1 - 1996 A1 - Michal Vieth A1 - Andrzej Koliński A1 - Jeffrey Skolnick KW - Amino Acid Sequence KW - Leucine Zippers KW - Molecular Sequence Data KW - Protein Folding AB - A method that employs a transfer matrix treatment combined with Monte Carlo sampling has been used to calculate the configurational free energies of folded and unfolded states of lattice models of proteins. The method is successfully applied to study the monomer-dimer equilibria in various coiled coils. For the short coiled coils, GCN4 leucine zipper, and its fragments, Fos and Jun, very good agreement is found with experiment. Experimentally, some subdomains of the GCN4 leucine zipper form stable dimeric structures, suggesting the regions of differential stability in the parent structure. Our calculations suggest that the stabilities of the subdomains are in general different from the values expected simply from the stability of the corresponding fragment in the wild type molecule. Furthermore, parts of the fragments structurally rearrange in some regions with respect to their corresponding wild type positions. Our results suggest for an Asn in the dimerization interface at least a pair of hydrophobic interacting helical turns at each side is required to stabilize the stable coiled coil. Finally, the specificity of heterodimer formation in the Fos-Jun system comes from the relative instability of Fos homodimers, resulting from unfavorable intra- and interhelical interactions in the interfacial coiled coil region. VL - 35 UR - http://www.ncbi.nlm.nih.gov/pubmed/8547278 ER - TY - JOUR T1 - On the origin of the cooperativity of protein folding: implications from model simulations JF - Proteins Y1 - 1996 A1 - Andrzej Koliński A1 - Wojciech Galazka A1 - Jeffrey Skolnick KW - Amino Acids KW - Amino Acids: chemistry KW - Chemical KW - Computer Simulation KW - Models KW - Molecular KW - Protein Conformation KW - Protein Folding KW - Thermodynamics AB - There is considerable experimental evidence that the cooperativity of protein folding resides in the transition from the molten globule to the native state. The objective of this study is to examine whether simplified models can reproduce this cooperativity and if so, to identify its origin. In particular, the thermodynamics of the conformational transition of a previously designed sequence (A. Kolinski, W. Galazka, and J. Skolnick, J. Chem. Phys. 103: 10286-10297, 1995), which adopts a very stable Greek-key beta-barrel fold has been investigated using the entropy Monte Carlo sampling (ESMC) technique of Hao and Scheraga (M.-H. Hao and H.A. Scheraga, J. Phys. Chem. 98: 9882-9883, 1994). Here, in addition to the original potential, which includes one body and pair interactions between side chains, the force field has been supplemented by two types of multi-body potentials describing side chain interactions. These potentials facilitate the protein-like pattern of side chain packing and consequently increase the cooperativity of the folding process. Those models that include an explicit cooperative side chain packing term exhibit a well-defined all-or-none transition from a denatured, random coil state to a high-density, well-defined, nativelike low-energy state. By contrast, models lacking such a term exhibit a conformational transition that is essentially continuous. Finally, an examination of the conformations at the free-energy barrier between the native and denatured states reveals that they contain a substantial amount of native-state secondary structure, about 50% of the native contacts, and have an average root mean square radius of gyration that is about 15% larger than native. VL - 26 SN - 1028610297 UR - http://www.ncbi.nlm.nih.gov/pubmed/8953649 ER - TY - Generic T1 - Prediction of the quaternary structure of coiled coils: GCN4 leucine zipper and its mutants. T2 - Proceeding of I-st Pacific Symposium on Biocomputing Y1 - 1996 A1 - Michal Vieth A1 - Andrzej Koliński A1 - Charles L. Brooks III A1 - Jeffrey Skolnick A1 - L. Hunter A1 - T. E. Klein KW - be addressed KW - gcn4 leucine zipper KW - multimeric equilibrium KW - protein folding simulations KW - Quaternary KW - quaternary structure stability KW - structure prediction AB - A methodology for predicting coiled coil quaternary structure and for the dissection of the interactions responsible for the global fold is described. Application is made to the equilibrium between different oligomeric species of the wild type GCN4 leucine zipper and seven of its mutants that were studied by Harbury et al. Over the entire experimental concentration range, agreement with experiment is found in five cases, while in two other cases, agreement is found over a portion of the concentration range. These simulations suggest that the degree of chain association is determined by the balance between specific side chain packing preferences and the entropy reduction associated with side chain burial in higher order multimers. JF - Proceeding of I-st Pacific Symposium on Biocomputing UR - http://ukpmc.ac.uk/abstract/MED/9390265 ER - TY - JOUR T1 - Solvent effects on nitrogen NMR shieldings in thiazole and thiadiazole systems JF - Journal of the Chemical Society, Perkin Transactions 2 Y1 - 1996 A1 - Michal Witanowski A1 - Wanda Sicinska A1 - Zenobia Biedrzycka A1 - Zbigniew Grabowski A1 - Graham A. Webb AB - High precision N NMR measurements are reported for all six possible thiazole and thiadiazole molecules in a variety of solvents. Both solvent polarity and hydrogen bonding effects on the nitrogen nuclear shielding of the solutes are significant. Both types of effect produce an increase in the solute nitrogen shielding. Analysis of the experimental data and molecular orbital studies indicate that an increase in the polarity of the solvent favours the delocalization of the lone pair electrons from the sulfur atoms into the conjugated rings. This leads to an increase in electronic charge at the nitrogen atom(s) concerned. This effect is more pronounced than analogous effects observed for pyridine type nitrogen atoms in the corresponding diazole and triazole systems. The significant shielding effects which result from solvent to solute hydrogen bonding to ring nitrogen atoms are shown to be essentially local in origin. Thus the shielding concerned is that of the nitrogen atom directly involved in the hydrogen bonding. PB - The Royal Society of Chemistry UR - http://dx.doi.org/10.1039/P29960000619 ER - TY - JOUR T1 - Solvent Effects on the Nitrogen NMR Shieldings in Oxazole and Oxadiazole Systems JF - Journal of Magnetic Resonance, Series A Y1 - 1996 A1 - Michal Witanowski A1 - Zenobia Biedrzycka A1 - Wanda Sicinska A1 - Zbigniew Grabowski A1 - Graham A. Webb AB - High-precision14N NMR shieldings are reported for all five available oxazoles and oxadiazoles in a variety of solvents. Both solvent polarity and hydrogen-bond effects on the nitrogen nuclear shieldings of the solutes are significant and comparable in magnitude; both give rise to shielding increases. The increasing solvent polarity favors delocalization of electrons from oxygen atoms into the heteroaromatic rings with a concomitant electron charge accumulation on the nitrogen atoms concerned. This trend is parallel to those found for analogous diazole and triazole heteroaromatic systems. Solvent-to-solute hydrogen bonding causes an increase in nitrogen shielding when the nitrogen atoms in question are involved in the hydrogen bonding as acceptor sites. This reflects not only local effects of hydrogen bonding to a particular nitrogen atom but also those arising from competition between other acceptor sites in a given molecule; these include oxygen and other nitrogen atoms. TNDO/2-calculated nitrogen shieldings, with respect to neat nitromethane, give a very good linear correlation with experimental results when all of the nitrogen atoms in the molecules studied are taken into account. The present study of nitrogen shieldings provides a valuable insight into solvent polarity effects on electric charge distribution in nitrogenous heteroaromatic systems, as well as into possible competition between various hydrogen-bond acceptor centers with respect to hydrogen-bond donor solvents. VL - 120 UR - http://www.sciencedirect.com/science/article/pii/S1064185896901126 ER - TY - JOUR T1 - Solvent effects on the nitrogen NMR shieldings of cyanamide and N,N-dimethyl cyanamide JF - Journal of Molecular Structure Y1 - 1996 A1 - Michal Witanowski A1 - Wanda Sicinska A1 - Zenobia Biedrzycka A1 - Graham A. Webb KW - Cyanamide KW - N KW - N-dimethyl cyanamide KW - NMR spectroscopy KW - Solvent effects AB - High precision N NMR measurements of solvent induced nitrogen shielding variations in both the NR2 and cyano moieties of cyanamide and of N,N-dimethylcyanamide are reported. The solvent induced shielding changes are much larger for the cyano, than for the NR2 groups. The NMe2 group has a nitrogen shielding which is almost invariant to choice of solvent. Solvent effects on the cyano groups of the compounds studied closely match those observed for simple alkyl cyanides. Overall analysis of the nitrogen shielding data favours a highly non-planar geometry for the compounds studied and no significant π electron conjugation between the NR2 and the cyano groups. VL - 380 UR - http://www.ingentaconnect.com/content/els/00222860/1996/00000380/00000001/art09205 ER - TY - JOUR T1 - Are proteins ideal mixtures of amino acids? Analysis of energy parameter sets JF - Protein Science: a Publication of the Protein Society Y1 - 1995 A1 - Adam Godzik A1 - Andrzej Koliński A1 - Jeffrey Skolnick KW - Amino Acid Sequence KW - Amino Acids KW - Crystallography KW - Databases KW - Factual KW - Magnetic Resonance Spectroscopy KW - Mathematics KW - Models KW - Protein Conformation KW - Protein Folding KW - Proteins KW - Proteins: chemistry KW - Theoretical KW - Thermodynamics KW - X-Ray AB - Various existing derivations of the effective potentials of mean force for the two-body interactions between amino acid side chains in proteins are reviewed and compared to each other. The differences between different parameter sets can be traced to the reference state used to define the zero of energy. Depending on the reference state, the transfer free energy or other pseudo-one-body contributions can be present to various extents in two-body parameter sets. It is, however, possible to compare various derivations directly by concentrating on the "excess" energy-a term that describes the difference between a real protein and an ideal solution of amino acids. Furthermore, the number of protein structures available for analysis allows one to check the consistency of the derivation and the errors by comparing parameters derived from various subsets of the whole database. It is shown that pair interaction preferences are very consistent throughout the database. Independently derived parameter sets have correlation coefficients on the order of 0.8, with the mean difference between equivalent entries of 0.1 kT. Also, the low-quality (low resolution, little or no refinement) structures show similar regularities. There are, however, large differences between interaction parameters derived on the basis of crystallographic structures and structures obtained by the NMR refinement. The origin of the latter difference is not yet understood. VL - 4 UR - http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2142984&tool=pmcentrez&rendertype=abstract ER - TY - JOUR T1 - Assessment of Solvent-Induced Nitrogen Shielding Variations of Triazole Systems JF - Journal of Magnetic Resonance, Series A Y1 - 1995 A1 - Michal Witanowski A1 - Wanda Sicinska A1 - Zenobia Biedrzycka A1 - Zbigniew Grabowski A1 - Graham A. Webb AB - High-precision 14N \{NMR\} shieldings are reported for all of the possible N-methyl triazoles in a variety of solvents. A large difference is observed in the effects of solvent on the shieldings of the pyrrole-type and pyridine-type nitrogen atoms in such systems. This difference largely arises from solvent-to-solute hydrogen-bonding effects for the latter type of nitrogen atom. For these two types of nitrogen atoms in triazoles, solvent polarity effects induce changes in the shieldings in opposite directions: this is corroborated by shielding calculations using the solvaton model. Solvent-to-solute hydrogen-bonding effects are larger than those due to solvent polarity and permit the assessment of the basicities of nonequivalent nitrogenous sites; these appear to parallel the analogous basicities with respect to protonation. VL - 112 UR - http://www.sciencedirect.com/science/article/pii/S1064185885710108 ER - TY - JOUR T1 - Computer design of idealized beta-motifs JF - Journal of Chemical Physics Y1 - 1995 A1 - Andrzej Koliński A1 - Wojciech Galazka A1 - Jeffrey Skolnick AB - A lattice model of protein conformation and dynamics is used to explore the requirements for the de novo folding from an arbitrary random coil state of idealized models of four and six-member b-barrels. A number of possible conjectures for the factors giving rise to the structural uniqueness of globular proteins are examined. These include the relative role of generic hydrophilic/ hydrophobic amino acid patterns, the relative importance of the specific identity of the hydrophobic amino acids that form the core of the protein and the possible role played by polar groups in destabilizing alternative, misfolded conformations. These studies may also provide some insights into the relative importance of short range interactions, cooperative hydrogen bonding and tertiary interactions in determining the uniqueness of the native state, as well as the cooperativity of the folding process. Thus, these simulations may provide guidelines for the early stages of the protein process. Possible applications to the general protein folding problem are also briefly discussed. © 1995 American Institute of Physics VL - 103 UR - http://smartech.gatech.edu/handle/1853/27034 ER - TY - JOUR T1 - De novo simulations of the folding of GCN4 and its mutants JF - Modeling of Biomolecular Structures and Mechanisms Y1 - 1995 A1 - Jeffrey Skolnick A1 - Michal Vieth A1 - Andrzej Koliński A1 - Charles L. Brooks III KW - Leucine Zippers/computer KW - Protein folding/GCN4 KW - protein models KW - simulations/lattice AB - A hierarchical approach to protein folding is employed to examine the folding pathway and predict the quaternary structure of the GCN4 leucine zipper. Structures comparable in quality to experiment have been predicted. In addition, the equilibrium between dimers, trimers and tetramers of a number of GCN4 mutants has been examined. In most of the cases, the simulation results are in accord with the experimental studies of Harbury et al. VL - 8 UR - http://cssb.biology.gatech.edu/skolnick/publications/pdffiles/124.pdf ER - TY - JOUR T1 - Neural network system for the evaluation of side-chain packing in protein structures JF - Protein Engineering Y1 - 1995 A1 - Mariusz Milik A1 - Andrzej Koliński A1 - Jeffrey Skolnick AB - An artificial neural network system is used for pattern recognition in protein side-chain-side-chain contact maps. A back-propagation network was trained on a set of patterns which are popular in side-chain contact maps of protein structures. Several neural network architectures and different training parameters were tested to decide on the best combination for the neural network. The resulting network can distinguish between original (from protein structures) and randomized patterns with an accuracy of 84.5% and a Matthews' coefficient of 0.72 for the testing set. Applications of this system for protein structure evaluation and refinement are also proposed. Examples include structures obtained after the application of molecular dynamics to crystal structures, structures obtained from X-ray crystallography at various stages of refinement, structures obtained from a de novo folding algorithm and deliberately misfolded structures. VL - 8 UR - http://peds.oxfordjournals.org/content/8/3/225.short ER - TY - JOUR T1 - Prediction of quaternary structure of coiled coils. Application to mutants of the GCN4 leucine zipper JF - Journal of Molecular Biology Y1 - 1995 A1 - Michal Vieth A1 - Andrzej Koliński A1 - Charles L. Brooks III A1 - Jeffrey Skolnick KW - Computer Simulation KW - DNA-Binding Proteins KW - Fungal Proteins KW - Fungal Proteins: chemistry KW - Hydrogen Bonding KW - Leucine Zippers KW - Monte Carlo Method KW - Mutation KW - Protein Conformation KW - Protein Folding KW - Protein Kinases KW - Protein Kinases: chemistry KW - Saccharomyces cerevisiae Proteins KW - Thermodynamics AB - Using a simplified protein model, the equilibrium between different oligomeric species of the wild-type GCN4 leucine zipper and seven of its mutants have been predicted. Over the entire experimental concentration range, agreement with experiment is found in five cases, while in two cases agreement is found over a portion of the concentration range. These studies demonstrate a methodology for predicting coiled coil quaternary structure and allow for the dissection of the interactions responsible for the global fold. In agreement with the conclusion of Harbury et al., the results of the simulations indicate that the pattern of hydrophobic and hydrophilic residues alone is insufficient to define a protein's three-dimensional structure. In addition, these simulations indicate that the degree of chain association is determined by the balance between specific side-chain packing preferences and the entropy reduction associated with side-chain burial in higher-order multimers. VL - 251 UR - http://www.ncbi.nlm.nih.gov/pubmed/7650742 ER - TY - JOUR T1 - A reduced model of short range interactions in polypeptide chains JF - Journal of Chemical Physics Y1 - 1995 A1 - Andrzej Koliński A1 - Mariusz Milik A1 - Jakub Rycombel A1 - Jeffrey Skolnick AB - A simple model of short range interactions is proposed for a reduced lattice representation of polypeptide conformation. The potential is derived on the basis of statistical regularities seen in the known crystal structures of globular proteins. This potential accounts for the generic stiffness of polypeptides, the correlation between peptide bond plates, and the sequence dependent correlations between consecutive segments of the Ca-trace. This model is used for simulation of the equilibrium and dynamic properties of polypeptides in the denatured state. It is shown that the proposed factorization of the local conformational propensities reproduces secondary structure tendencies encoded in the protein sequence. Possible applications for modeling of protein folding are briefly discussed. © 1995 American Institute of Physics. VL - 103 UR - http://smartech.gatech.edu/handle/1853/27082 ER - TY - JOUR T1 - A simple technique to estimate partition functions and equilibrium constants from Monte Carlo simulations JF - Journal of Chemical Physics Y1 - 1995 A1 - Michal Vieth A1 - Andrzej Koliński A1 - Jeffrey Skolnick KW - equilibrium KW - factorization KW - molecules KW - Monte Carlo Method KW - partition functions KW - simulation KW - statistical mechanics AB - A combined Monte Carlo (MC) simulation‐statistical mechanical treatment is proposed to calculate the internal partition function and equilibrium constant. The method has been applied to a number of one and multidimensional analytical functions. When sampling is incomplete, various factorization approximations for estimating the partition function are discussed. The resulting errors are smaller when the ratios of the partition functions are calculated (as in the determination of equilibrium constants) as opposed to the partition function itself. © 1995 American Institute of Physics. VL - 102 UR - http://smartech.gatech.edu/handle/1853/27021 ER - TY - JOUR T1 - De Novo Prediction of Protein Tertiary Structure JF - Polymer Preprints Y1 - 1994 A1 - Jeffrey Skolnick A1 - Andrzej Koliński VL - 35 ER - TY - JOUR T1 - Dynamics of star branched polymers in a matrix of linear chains—a Monte Carlo study JF - Macromolecular Theory and Simulations Y1 - 1994 A1 - Andrzej Sikorski A1 - Andrzej Koliński A1 - Jeffrey Skolnick AB - A simple cubic lattice model of the melt of 3-arm star-branched polymers of various length dissolved in a matrix of long linear chains (n1 = 800 beads) is studied using a dynamic Monte Carlo method. The total polymer volume fraction is equal to 0,5, while the volume fraction of the star polymers is about ten times smaller. The static and dynamic properties of these systems are compared with the corresponding model systems of isolated star-branched polymers and with the melt of linear chains. It has been found that the number of dynamic entanglements for the star polymers with arm length up to 400 segments is too small for the onset of the arm retraction mechanism of polymer relaxation. In this regime dynamics of star-branched polymers is close to the dynamics of linear polymers at corresponding concentration and with equivalent chain length. The entanglement length for star polymers appears to be somewhat larger compared with linear chains. VL - 3 UR - http://onlinelibrary.wiley.com/doi/10.1002/mats.1994.040030407/abstract ER - TY - JOUR T1 - Monte Carlo simulations of protein folding. I. Lattice model and interaction scheme JF - Proteins Y1 - 1994 A1 - Andrzej Koliński A1 - Jeffrey Skolnick KW - Amino Acid Sequence KW - Amino Acids KW - Computer Simulation KW - Hydrogen Bonding KW - Models, Chemical KW - Models, Molecular KW - Models, Theoretical KW - Molecular Sequence Data KW - Monte Carlo Method KW - Protein Folding KW - Protein Structure, Tertiary AB - A new hierarchical method for the simulation of the protein folding process and the de novo prediction of protein three-dimensional structure is proposed. The reduced representation of the protein alpha-carbon backbone employs lattice discretizations of increasing geometrical resolution and a single ball representation of side chain rotamers. In particular, coarser and finer lattice backbone descriptions are used. The coarser (finer) lattice represents C alpha traces of native proteins with an accuracy of 1.0 (0.7) A rms. Folding is simulated by means of very fast Monte Carlo lattice dynamics. The potential of mean force, predominantly of statistical origin, contains several novel terms that facilitate the cooperative assembly of secondary structure elements and the cooperative packing of the side chains. Particular contributions to the interaction scheme are discussed in detail. In the accompanying paper (Kolinski, A., Skolnick, J. Monte Carlo simulation of protein folding. II. Application to protein A, ROP, and crambin. Proteins 18:353-366, 1994), the method is applied to three small globular proteins. VL - 18 IS - 4 ER - TY - JOUR T1 - Monte Carlo Simulations of Protein Folding. I. Lattice Model nad Interaction Scheme JF - Proteins Y1 - 1994 A1 - Jeffrey Skolnick KW - crambin KW - difficult KW - duced protein model KW - lattice pro- KW - molten glob- KW - pro- KW - protein a KW - protein folding em- KW - proven to be extremely KW - re- KW - tein folding pathways KW - tertiary structure prediction KW - ule state KW - various computer models of VL - 18 ER - TY - JOUR T1 - Monte Carlo simulations of protein folding. II. Application to protein A, ROP, and crambin JF - Proteins: Structure, Function, Bioinformatics Y1 - 1994 A1 - Andrzej Koliński A1 - Jeffrey Skolnick KW - crambin KW - molten glob- KW - pro- KW - protein a KW - tein folding pathways KW - tertiary structure prediction KW - ule state AB - The hierarchy of lattice Monte Carlo models described in the accompanying paper (Kolinski, A., Skolnick, J. Monte Carlo simulations of protein folding. I. Lattice model and interaction scheme. Proteins 18:338-352, 1994) is applied to the simulation of protein folding and the prediction of 3-dimensional structure. Using sequence information alone, three proteins have been successfully folded: the B domain of staphylococcal protein A, a 120 residue, monomeric version of ROP dimer, and crambin. Starting from a random expanded conformation, the model proteins fold along relatively well-defined folding pathways. These involve a collection of early intermediates, which are followed by the final (and rate-determining) transition from compact intermediates closely resembling the molten globule state to the native-like state. The predicted structures are rather unique, with native-like packing of the side chains. The accuracy of the predicted native conformations is better than those obtained in previous folding simulations. The best (but by no means atypical) folds of protein A have a coordinate rms of 2.25 A from the native C alpha trace, and the best coordinate rms from crambin is 3.18 A. For ROP monomer, the lowest coordinate rms from equivalent C alpha s of ROP dimer is 3.65 A. Thus, for two simple helical proteins and a small alpha/beta protein, the ability to predict protein structure from sequence has been demonstrated. VL - 18 UR - http://onlinelibrary.wiley.com/doi/10.1002/prot.340180406/abstract ER - TY - JOUR T1 - Prediction of the Folding Pathways and Structure of the GCN4 Leucine Zipper JF - Journal of Molecular Biology Y1 - 1994 A1 - Michal Vieth A1 - Andrzej Koliński A1 - Charles L. Brooks III A1 - Jeffrey Skolnick KW - coiled coils AB - A hierarchical approach is described for the prediction of the three-dimensional structure and folding pathway of the GCN4 leucine zipper. Dimer assembly is simulated by Monte Carlo dynamics. The resulting lowest energy structures undergo cooperative rearrangement of their hydrophobic core leading to side-chain fixation. The coarse-grained structures are further refined using a molecular dynamics annealing protocol. This produces full atom models with a backbone root-mean-square deviation from the crystal structure of 0.81 A. Thus, we demonstrate the predictive ability of our approach to yield high resolution structures of small coiled coils from their sequence. VL - 237 UR - http://www.sciencedirect.com/science/article/pii/S0022283684712393 ER - TY - JOUR T1 - Solvent induced nitrogen NMR shielding variation of α-phenyl-N-methylnitrone JF - Journal of Molecular Structure Y1 - 1994 A1 - Michael Witanowski A1 - Wanda Sicinska A1 - Graham A. Webb AB - Nitrogen NMR shieldings of phenyl-N-methylnitrone are shown to be quite sensitive to solvent effects. The dominant contribution to the solvent induced range of nitrogen shieldings is produced by the hydrogen bond donor ability of the solvents. This indicates that hydrogen bonding to an oxygen atom contiguous with a nitrogen atom can exert effects on the nitrogen shielding which are comparable with those exerted by direct hydrogen bonding to the nitrogen lone pair electrons in imine systems. Minor shielding changes due to solvent polarity polarizability are quite well reproduced by nitrogen shielding calculations incorporating the solvation model. VL - 321 UR - http://www.sciencedirect.com/science/article/pii/002228609307941O ER - TY - JOUR T1 - Solvent induced nitrogen NMR shielding variations of some covalent isocyanates JF - Journal of Molecular Structure Y1 - 1994 A1 - Michal Witanowski A1 - Zenobia Biedrzycka A1 - Wanda Sicinska A1 - Graham A. Webb AB - Investigations of solvent-induced nitrogen shielding variations for three covalent isocyanates show that the small changes observed are governed mainly by solvent polarity effects. A less significant contribution arises from solvent to solute hydrogen bonding, since the two contributions are of opposite signs, the overall range of solvent induced changes in the nitrogen shieldings of covalent isocyanates is relatively small compared with those of C=N moieties contained in imino-type structures or heteroaromatic rings. Solvaton model nitrogen shielding calculations support the observed signs of the solvent polarity effects exhibited by the nitrogen shieldings of these groups of molecules. Analysis of the observed nitrogen shielding variations with respect to a change of solvent shows that oxygen, rather than nitrogen, is the preferred site for solvent-to-solute hydrogen bonding in the covalent isocyanates. VL - 328 UR - http://www.sciencedirect.com/science/article/pii/0022286094083851 ER - TY - JOUR T1 - A Study of Solvent Effects on the NMR Shieldings of the Two Types of Nitrogen Atoms Contained in Diazole Ring Systems JF - Journal of Magnetic Resonance, Series A Y1 - 1994 A1 - Michal Witanowski A1 - Wanda Sicinska A1 - Zenobia Biedrzycka A1 - Graham A. Webb AB - The diazole ring systems, N-methyl derivatives of pyrazole and imidazole, show a clear differentiation between pyrrole and pyridine types of nitrogen atoms from the point of view of their solvent-induced nitrogen shielding variations. The largest effects on the nitrogen shieldings derive from hydrogen bonding from solvent to solute, which involve the lone pair electrons at the pyridine-type nitrogen atoms of the solute. These effects may be used to identify sites of hydrogen-bond accepters in the solute molecules. Solvent-polarity effects on the nitrogen shieldings suggest a significant charge migration from pyrrole- to pyridine-type nitrogen atoms in such systems. Solvaton calculations amply support this proposal by correctly predicting the observed directions and relative magnitudes of the nitrogen shielding variations as a function of solvent polarity. VL - 109 UR - http://www.sciencedirect.com/science/article/pii/S1064185884711521 ER - TY - JOUR T1 - The unexpectedly low sensitivity of the nitrogen NMR shieldings of covalent azides to solvent effects JF - International Journal of Spectroscopy Y1 - 1994 A1 - Michal Witanowski A1 - Wanda Sicinska A1 - Graham A. Webb VL - 12 ER - TY - JOUR T1 - Comment on "Local knot model of entangled polymer chains" JF - The Journal of Physical Chemistry Y1 - 1993 A1 - Andrzej Koliński A1 - Jeffrey Skolnick VL - 97 UR - http://pubs.acs.org/doi/abs/10.1021/j100115a059 ER - TY - JOUR T1 - De novo and inverse folding predictions of protein structure and dynamics JF - Journal of Computer-Aided Molecular Design Y1 - 1993 A1 - Adam Godzik A1 - Andrzej Koliński A1 - Jeffrey Skolnick KW - Inverse folding KW - lattice protein models KW - Molten globule intermediates KW - Protein folding pathways KW - tertiary structure prediction AB - In the last two years, the use of simplified models has facilitated major progress in the globular protein folding problem, viz., the prediction of the three-dimensional (3D) structure of a globular protein from its amino acid sequence. A number of groups have addressed the inverse folding problem where one examines the compatibility of a given sequence with a given (and already determined) structure. A comparison of extant inverse protein-folding algorithms is presented, and methodologies for identifying sequences likely to adopt identical folding topologies, even when they lack sequence homology, are described. Extension to produce structural templates or fingerprints from idealized structures is discussed, and for eight-membered beta-barrel proteins, it is shown that idealized fingerprints constructed from simple topology diagrams can correctly identify sequences having the appropriate topology. Furthermore, this inverse folding algorithm is generalized to predict elements of supersecondary structure including beta-hairpins, helical hairpins and alpha/beta/alpha fragments. Then, we describe a very high coordination number lattice model that can predict the 3D structure of a number of globular proteins de novo; i.e. using just the amino acid sequence. Applications to sequences designed by DeGrado and co-workers [Biophys. J., 61 (1992) A265] predict folding intermediates, native states and relative stabilities in accord with experiment. The methodology has also been applied to the four-helix bundle designed by Richardson and co-workers [Science, 249 (1990) 884] and a redesigned monomeric version of a naturally occurring four-helix dimer, rop. Based on comparison to the rop dimer, the simulations predict conformations with rms values of 3-4 A from native. Furthermore, the de novo algorithms can assess the stability of the folds predicted from the inverse algorithm, while the inverse folding algorithms can assess the quality of the de novo models. Thus, the synergism of the de novo and inverse folding algorithm approaches provides a set of complementary tools that will facilitate further progress on the protein-folding problem. VL - 7 UR - http://www.springerlink.com/index/QM35800826224081.pdf ER - TY - JOUR T1 - A detailed 1H and 13C NMR study of a repeating disaccharide of hyaluronan: the effects of temperature and counterion type JF - Carbohydrate Research Y1 - 1993 A1 - Wanda Sicinska A1 - Bruce Adams A1 - Laura Lerner AB - For the first time, a detailed NMR study of the conformation of methyl 2-acetamido-2-deoxy-3-O-(β-d-glucopyranosyluronic acid)-β-d-glucopyranoside (dissacharide 1) in aqueous solution is reported. This disaccharide is a repeating unit of hyaluronan, a polysaccharide with widespread biological and pharmaceutical applications. Relatively small changes in temperature, over typical experimental conditions (0–37°C), completely change the appearance of its one-dimensional 1H NMR spectrum at 500 MHz. To determine the underlying cause for this temperature sensitivity, we analyzed 1H and 13C chemical shifts, temperature coefficients (Δδ/ΔT), 1H-1H coupling constants, and interglycosidic 1H-13C coupling constants for 1 as a function of temperature. For comparison, we measured the temperature dependence of 1H chemical shifts and coupling constants for related monosaccharides: glucuronate (GlcUA or U) and N-acetylglucosamine (GlcNAc or N), and glucose (Glc). The temperature sensitivity of the 1H spectrum of 1 is caused by relatively larger values of Δδ/ΔT for some ring protons, rather than a conformational change. The effect is mediated by strong coupling. To detect the presence of long-lived intramolecular hydrogen bonds in the disaccharide, we measured chemical shifts, Δδ/ΔT, and coupling constants for hydroxyl protons of 1, GlcUA, and GlcNAc in 1:1H2O-acetone-d6 at low temperature. We compared 1H NMR parameters for 1, GlcUA, and GlcNAc in water with published values measured in Me2SO-d6 and concluded that interactions with water predominated. We found no evidence for long-lived intramolecular hydrogen bonds occurring in 1 in aqueous solution. VL - 242 UR - http://www.sciencedirect.com/science/article/pii/000862159380020F ER - TY - JOUR T1 - From independent modules to molten globules: observations on the nature of protein folding intermediates JF - Proceedings of the National Academy of Sciences of the United States of America Y1 - 1993 A1 - Jeffrey Skolnick A1 - Andrzej Koliński A1 - Adam Godzik KW - Binding Sites KW - Isomerases KW - Isomerases: chemistry KW - Protein Disulfide-Isomerases KW - Protein Folding KW - Protein Structure KW - Proteins KW - Proteins: chemistry KW - Secondary VL - 90 UR - http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=46030&tool=pmcentrez&rendertype=abstract ER - TY - JOUR T1 - A general method for the prediction of the three dimensional structure and folding pathway of globular proteins: Application to designed helical proteins JF - The Journal of Chemical Physics Y1 - 1993 A1 - Andrzej Koliński A1 - Adam Godzik A1 - Jeffrey Skolnick KW - Amino Acid Sequence KW - GLOBULAR proteins AB - Starting from amino acid sequence alone, a general approach for simulating folding into the molten globule or rigid, native state depending on sequence is described. In particular, the 3D folds of two simple designed proteins have been predicted using a Monte Carlo folding algorithm. The model employs a very flexible hybrid lattice representation of the protein conformation, and fast lattice dynamics. A full rotamer library for side group conformations, and potentials of mean force of short and long range interactions have been extracted from the statistics of a high resolution set of nonhomologous, 3D structures of globular proteins. The simulated folding process starts from an arbitrary random conformation and relatively rapidly assembles a well defined four helix bundle. The very cooperative folding of the model systems is facilitated by the proper definition of the model protein hydrogen bond network, and multibody interactions of the side groups. The two sequences studied exhibit very different behavior. The first one, in excellent agreement with experiment, folds to a thermodynamically very stable four helix bundle that has all the properties postulated for the molten globule state. The second protein, having a more heterogeneous sequence, at lower temperature undergoes a transition from the molten globule state to the unique native state exhibiting a fixed pattern of side group packing. This marks the first time that the ability to predict a molten globule or a unique native state from sequence alone has been achieved. The implications for the general solution of the protein folding problem are briefly discussed. VL - 98 UR - http://smartech.gatech.edu/handle/1853/26987 http://link.aip.org/link/JCPSA6/v98/i9/p7420/s1&Agg=doi ER - TY - JOUR T1 - A lattice dynamics study of a Langmuir monolayer fatty acids JF - Journal of Chemical Physics Y1 - 1993 A1 - Yehudi K. Levine A1 - Andrzej Koliński A1 - Jeffrey Skolnick AB - A Monte Carlo dynamics (MCD) scheme has been applied in a study of the effects of unsaturated double bonds on the internal conformational dynamics and orientational order of hydrocarbon chains arranged in a monolayer on the surface of an impenetrable interface. The MCD algorithm makes use of the high coordination {2 1 0} lattice for the representation of both sp3 and sp2 valence states of the carbon atoms. The chain dynamics are considered to arise from a superposition of local conformational rearrangements. The simulations reproduced the principal features of the experimentally observed order parameter profiles of the C–H bonds on taking into account the intramolecular conformational energy of the molecules and excluded volume effects. The results show that the introduction of a rigid, planar, unsaturated segment enhances the orientational order in the monolayer. The extent of the enhancement is larger for the trans unsaturated chains than for the cis unsaturated ones. The increase in orientational order is accompanied by a marked increase in the effective rotational correlation times, indicating that the unsaturated segments undergo slow and restricted motion. In addition, the C–H bonds of the saturated chain segment between the cis double bond and the headgroup of the chain undergo slower motions than the corresponding vectors in the saturated and trans unsaturated chains. This arises from the anchoring of the headgroup at the impenetrable monolayer interface. VL - 98 ER - TY - JOUR T1 - Lattice representations of globular proteins: How good are they? JF - Journal of Computational Chemistry Y1 - 1993 A1 - Adam Godzik A1 - Andrzej Koliński A1 - Jeffrey Skolnick AB - Using a number of different lattice models of proteins, the problems introduced by the discretization of a protein backbone are discussed and examples of the most typical errors arising in low coordination number lattices presented. The geometric properties of different lattices used in the literature are compiled, and for all of them the resulting α-carbon models of proteins are described in detail and compared to the original structures obtained from experiment. © John Wiley & Sons, Inc. VL - 14 UR - http://onlinelibrary.wiley.com/doi/10.1002/jcc.540141009/abstract ER - TY - JOUR T1 - A method for prediction of protein structure from sequence JF - Current Biology Y1 - 1993 A1 - Jeffrey Skolnick A1 - Andrzej Koliński A1 - Charles L. Brooks III A1 - Adam Godzik A1 - Antonio Rey AB - BACKGROUND: The ability to predict the native conformation of a globular protein from its amino-acid sequence is an important unsolved problem of molecular biology. We have previously reported a method in which reduced representations of proteins are folded on a lattice by Monte Carlo simulation, using statistically-derived potentials. When applied to sequences designed to fold into four-helix bundles, this method generated predicted conformations closely resembling the real ones. RESULTS: We now report a hierarchical approach to protein-structure prediction, in which two cycles of the above-mentioned lattice method (the second on a finer lattice) are followed by a full-atom molecular dynamics simulation. The end product of the simulations is thus a full-atom representation of the predicted structure. The application of this procedure to the 60 residue, B domain of staphylococcal protein A predicts a three-helix bundle with a backbone root mean square (rms) deviation of 2.25-3 A from the experimentally determined structure. Further application to a designed, 120 residue monomeric protein, mROP, based on the dimeric ROP protein of Escherichia coli, predicts a left turning, four-helix bundle native state. Although the ultimate assessment of the quality of this prediction awaits the experimental determination of the mROP structure, a comparison of this structure with the set of equivalent residues in the ROP dime- crystal structure indicates that they have a rms deviation of approximately 3.6-4.2 A. CONCLUSION: Thus, for a set of helical proteins that have simple native topologies, the native folds of the proteins can be predicted with reasonable accuracy from their sequences alone. Our approach suggest a direction for future work addressing the protein-folding problem. VL - 3 UR - http://dx.doi.org/10.1016/0960-9822(93)90348-R ER - TY - JOUR T1 - Pyrrole and N-Methylpyrrole as Models for Solvent Polarity and Solute-to-Solvent Hydrogen-Bonding Effects on Nitrogen NMR Shielding JF - Journal of Magnetic Resonance, Series A Y1 - 1993 A1 - Michal Witanowski A1 - Wanda Sicinska A1 - Zbigniew Grabowski A1 - Graham A. Webb AB - Nitrogen NMR shieldings of pyrrole-type nitrogen atoms are shown to be quite sensitive to solvent effects and seem to provide a means of insight into solvent-induced electron charge redistribution in five-membered heteroaromatic systems. Significant deshielding effects on the nitrogen nucleus are observed upon the formation of NH-to-solvent hydrogen bonds and, independently, upon the increasing solvent polarity, and this behavior is reproduced by quantum-mechanical calculations. A clear distinction is found between pyrrole-type and pyridine-type nitrogens from the point of view of the directions of solvent effects on the respective nitrogen shieldings. N-Methylpyrrole nitrogen shieldings in solutions are shown to provide a probe for an empirical scale of solvent polarity. VL - 104 UR - http://www.sciencedirect.com/science/article/pii/S1064185883712271 ER - TY - JOUR T1 - Regularities in interaction patterns of globular proteins JF - Protein Engineering Y1 - 1993 A1 - Adam Godzik A1 - Jeffrey Skolnick A1 - Andrzej Koliński AB - The description of protein structure in the language of side chain contact maps is shown to offer many advantages over more traditional approaches. Because it focuses on side chain interactions, it aids in the discovery, study and classification of similarities between interactions defining particular protein folds and offers new insights into the rules of protein structure. For example, there is a small number of characteristic patterns of interactions between protein supersecondary structural fragments, which can be seen in various non-related proteins. Furthermore, the overlap of the side chain contact maps of two proteins provides a new measure of protein structure similarity. As shown in several examples, alignments based on contact map overlaps are a powerful alternative to other structure-based alignments. VL - 6 UR - http://peds.oxfordjournals.org/content/6/8/801.short ER - TY - JOUR T1 - Solvent versus substituent effects on the nitrogen NMR shielding of the nitro-group in substituted benzenes JF - Magnetic Resonance in Chemistry Y1 - 1993 A1 - Michal Witanowski A1 - Wanda Sicinska A1 - Zenobia Biedrzycka A1 - Graham A. Webb KW - 14N shielding KW - Solvent and substituent effects KW - Substituted nitrobenzenes AB - Intermolecular effects are shown to induce a variation of about 5 ppm in the nitrogen NMR shieldings of aromatic nitro groups. The latter turn out to be comparable to those exerted by substituents in nitrobenzene derivatives in solutions in a given solvent. Substituent effects on the NO2 nitrogen shielding in nitro benzenes, in a given solvent, seem to reflect contributions from the so-called field-inductive effects on the electron charge distribution in such systems, and are insensitive to the resonance effects concerned with the delocalized pπ-electron systems involved. PB - John Wiley & Sons, Ltd. VL - 31 UR - http://dx.doi.org/10.1002/mrc.1260311008 ER - TY - JOUR T1 - Discretized model of proteins. I. Monte Carlo study of cooperativity in homopolypeptides JF - Journal of Chemical Physics Y1 - 1992 A1 - Andrzej Koliński A1 - Jeffrey Skolnick KW - Conformational Changes KW - Coupling KW - Globular Clusters KW - Lattice Gas KW - Molecular Models KW - Monte Carlo Method KW - Polypeptides KW - Proteins KW - Randomness KW - Resolution AB - A discretized model of globular proteins is employed in a Monte Carlo study of the helix–coil transition of polyalanine and the collapse transition of polyvaline. The present lattice realization permits real protein crystal structures to be represented at the level of 1 Å resolution. Furthermore, the Monte Carlo dynamic scheme is capable of moving elements of assembled secondary and supersecondary structure. The potentials of mean force for the interactions are constructed from the statistics of a set of high resolution x‐ray structures of nonhomologous proteins. The cooperativity of formation of ordered structures is found to be larger when the major contributions to the conformational energy of the low temperature states come from hydrogen bonds and short range conformational propensities. The secondary structure seen in the folded state is the result of an interplay between the short and long range interactions. Compactness itself, driven by long range, nonspecific interactions, seems to be insufficient to generate any appreciable secondary structure. A detailed examination of the dynamics of highly helical model proteins demonstrates that all elements of secondary structure are mobile in the present algorithm, and thus the folding pathways do not depend on the use of a lattice approximation. Possible applications of the present model to the prediction of protein 3D structures are briefly discussed. VL - 97 UR - http://link.aip.org/link/doi/10.1063/1.463317 ER - TY - JOUR T1 - Effect of double bonds on the dynamics of hydrocarbon chains JF - Journal of Chemical Physics Y1 - 1992 A1 - Antonio Rey A1 - Andrzej Koliński A1 - Jeffrey Skolnick A1 - Yehudi K. Levine KW - Algorithms KW - Brownian Movement KW - Chains KW - Coupling KW - Double Bonds KW - dynamics KW - equilibrium KW - Hydrocarbons KW - Monte Carlo Method KW - Relaxation KW - Saturation KW - simulation KW - Torsion AB - Brownian dynamics simulations of isolated 18‐carbon chains have been performed, both for saturated and unsaturated hydrocarbons. The effect of one or several (nonconjugated) double bonds on the properties of the chains is discussed in terms of both equilibrium and dynamic properties. The introduction of a cis double bond increases the relaxation rates of the unsaturated chain with respect to the saturated alkane. On the other hand, coupling effects in the torsional transitions around a trans double bond make the dynamics of this unsaturated chain very similar to the saturated one. Based on these results, the parameters and moves of a dynamic Monte Carlo algorithm are tuned to reproduce the observed behavior, providing an efficient method for the study of more complicated systems. VL - 97 UR - http://smartech.gatech.edu/handle/1853/26936 ER - TY - JOUR T1 - Medium effects on the nitrogen nuclear magnetic resonance shielding of acetone N-methylimine in solutions JF - International Journal of Spectroscopy Y1 - 1992 A1 - Michal Witanowski A1 - Wanda Sicinska A1 - Graham A. Webb VL - 10 ER - TY - JOUR T1 - Monte Carlo studies of an idealized model of a lipid-water system JF - The Journal of Physical Chemistry Y1 - 1992 A1 - Mariusz Milik A1 - Jeffrey Skolnick A1 - Andrzej Koliński AB - Employing Monte Carlo dynamics, the equilibrium and dynamic properties of lipid-water systems are studied in the context of a diamond lattice realization. The model faithfully describes the lipid molecule geometry and reproduces the essential physical properties of real membranes. These include the phase transitions from quasi-crystalline phase - liquid bilayer nonbilayer, quasi-hexagonal phase - dissolved liquid solution. Furthermore, the structure, ordering, and dynamics of the model liquid bilayer are in good accord with experiment, and the values of segmental ordering parameters are close to those obtained from NMR data. Due to the diamond lattice representation and a very efficient simulation algorithm, the intermediate distance scale dynamic features of the water-lipid system could be examined; these include lateral diffusion in the bilayer, the formation of a nonbilayer phase, the transbilayer diffusion of the lipid molecule, and the diffusion of a lipid molecule in the water phase. The present model can be also used to generate initial configurations for more detailed molecular (or Brownian) dynamics studies of lipid-water systems. VL - 96 UR - http://pubs.acs.org/doi/abs/10.1021/j100189a020 ER - TY - JOUR T1 - N,N’-Dicyclocarbodiimide as a model for solvent polarity effects on nitrogen shielding JF - International Journal of Spectroscopy Y1 - 1992 A1 - Michal Witanowski A1 - Wanda Sicinska A1 - Graham A. Webb VL - 10 ER - TY - JOUR T1 - Prediction of protein secondary structure by neural networks: encoding short and long range patterns of amino acid packing JF - Acta Biochimica Polonica Y1 - 1992 A1 - Michal Vieth A1 - Andrzej Koliński A1 - Jeffrey Skolnick A1 - Andrzej Sikorski AB - A complex, cascaded neural network designed to predict the secondary structure of globular proteins has been developed. Information about the local buried-unburied pattern and the average tendency of the particular types of amino acids to be buried inside the globule were used. Nonspecific information about long distance contact maps was also employed. These modifications result in a noticeable improvement (3-9%) of prediction accuracy. The best result for the average success ratio for the testing set of nonhomologous proteins was 68.3% (with corresponding Matthews' coefficients, C alpha,beta,coil equal to 0.60, 0.47, 0.43, respectively). VL - 39 UR - http://www.actabp.pl/pdf/4\_1992/369.pdf ER - TY - JOUR T1 - Simulations of the Folding Pathway of TIM-type a/ß Barrel Proteins JF - Proceedings of the National Academy of Sciences of the United States of America Y1 - 1992 A1 - Adam Godzik A1 - Jeffrey Skolnick A1 - Andrzej Koliński AB - Simulations of the folding pathways of two large alpha/beta proteins, the alpha subunit of tryptophan synthase and triose phosphate isomerase, are reported using the knight's walk lattice model of globular proteins and Monte Carlo dynamics. Starting from randomly generated unfolded states and with no assumptions regarding the nature of the folding intermediates, for the tryptophan synthase subunit these simulations predict, in agreement with experiment, the existence and location of a stable equilibrium intermediate comprised of six beta strands on the amino terminus of the molecule. For the case of triose phosphate isomerase, the simulations predict that both amino- and carboxyl-terminal intermediates should be observed. In a significant modification of previous lattice models, this model includes a full heavy atom side chain description and is capable of representing native conformations at the level of 2.5- to 3-A rms deviation for the C alpha positions, as compared to the crystal structure. With a well-balanced compromise between accuracy of the protein description and the computer requirements necessary to perform simulations spanning biologically significant amounts of time, the lattice model described here brings the possibility of studying important biological processes to present-day computers. VL - 89 ER - TY - JOUR T1 - Solvent effects on nitrogen NMR shieldings of 1,2,4-triazine JF - Journal of Magnetic Resonance (1969) Y1 - 1992 A1 - Michal Witanowski A1 - Wanda Sicinska A1 - Graham A. Webb AB - Nitrogen NMR shieldings of 1,2,4-triazine are shown, as an example, to be capable of providing deep insight into solvent-induced, site-oriented electric charge redistributions and solvent-solute hydrogen bonding effects in an unsymmetrical molecule. A sharp contrast is observed in the solvent effects on the nitrogen atoms in positions 1 and 2 with respect to that at position 4. The former pair of atoms exhibits a remarkable affinity to hydrogenbond donor solvents. Their electron densities appear to be significantly dependent upon the solvent polarity. In contrast N4 appears to be relatively uninfluenced by solvent effects. VL - 98 UR - http://www.sciencedirect.com/science/article/pii/002223649290113L ER - TY - JOUR T1 - Solvent-induced variations in nitrogen NMR shieldings of tert-butyl isocyanide as a probe for solvent polarizability–polarity JF - Magnetic Resonance in Chemistry Y1 - 1992 A1 - Michal Witanowski A1 - Wanda Sicinska A1 - Graham A. Webb KW - Nitrogen NMR shielding KW - Solvent polarizability–polarity KW - Solvent-induced variations KW - tert-Butyl isocyanide AB - The nitrogen NMR shielding of tert-butyl isocyanide (1) is shown to be a sensitive probe of solvent polarizability–polarity, since the shielding is demonstrated to be unresponsive to hydrogen bonding effects between 1 and the solvent. The direction of solvent effects observed is explained in terms of the solvaton model, used within the INDO/S–SOS framework. A comparison is made with solvent-induced nitrogen shielding variations of the corresponding isomeric covalent cyanides. PB - John Wiley & Sons, Ltd. VL - 30 UR - http://dx.doi.org/10.1002/mrc.1260300214 ER - TY - JOUR T1 - A Topology Fingerprint Approach to the Inverse Protein Folding Problem JF - Journal of Molecular Biology Y1 - 1992 A1 - Adam Godzik A1 - Jeffrey Skolnick A1 - Andrzej Koliński KW - globin-phycocyanin similarity KW - plastocyanin-azurin-immunoglobulin similarity KW - protein stability KW - protein structure prediction KW - TIM barrel similarity AB - We describe the most general solution to date of the problem of matching globular protein sequences to the appropriate three-dimensional structures. The screening template, against which sequences are tested, is provided by a protein "structural fingerprint" library based on the contact map and the buried/exposed pattern of residues. Then, a lattice Monte Carlo algorithm validates or dismisses the stability of the proposed fold. Examples of known structural similarities between proteins having weakly or unrelated sequences such as the globins and phycocyanins, the eight-member alpha/beta fold of triose phosphate isomerase and even a close structural equivalence between azurin and immunoglobulins are found. VL - 227 UR - http://dx.doi.org/10.1016/0022-2836(92)90693-E ER - TY - JOUR T1 - Collapse Transition of Semiflexible Polymers in 2-dimensional Systems JF - Acta Physica Polonica Y1 - 1991 A1 - Andrzej Koliński A1 - Michal Vieth A1 - Andrzej Sikorski VL - 79 ER - TY - JOUR T1 - Dinitrogen as a possible internal standard for nitrogen nuclear magnetic resonance JF - International Journal of Spectroscopy Y1 - 1991 A1 - Michal Witanowski A1 - Wanda Sicinska A1 - S. Biernat A1 - Graham A. Webb VL - 9 ER - TY - JOUR T1 - Dynamic Monte Carlo Simulations of a new lattice model of globular protein folding, structure, and dynamics JF - Journal of Molecular Biology Y1 - 1991 A1 - Jeffrey Skolnick A1 - Andrzej Koliński KW - assembly mechanism KW - bends and turns KW - folding pathways KW - Protein Folding KW - secondary structures AB - A long-standing problem of molecular biology is the prediction of globular protein tertiary structure from the primary sequence. In the context of a new, 24-nearest-neighbor lattice model of proteins that includes both alpha and beta-carbon atoms, the requirements for folding to a unique four-member beta-barrel, four-helix bundles and a model alpha/beta-bundle have been explored. A number of distinct situations are examined, but the common requirements for the formation of a unique native conformation are tertiary interactions plus the presence of relatively small (but not irrelevant) intrinsic turn preferences that select out the native conformer from a manifold of compact states. When side-chains are explicitly included, there are many conformations having the same or a slightly greater number of side-chain contacts as in the native conformation, and it is the local intrinsic turn preferences that produce the conformational selectivity on collapse. The local preference for helix or beta-sheet secondary structure may be at odds with the secondary structure ultimately found in the native conformation. The requisite intrinsic turn populations are about 0.3% for beta-proteins, 2% for mixed alpha/beta-proteins and 6% for helix bundles. In addition, an idealized model of an allosteric conformational transition has been examined. Folding occurs predominantly by a sequential on-site assembly mechanism with folding initiating either at a turn or from an isolated helix or beta-strand (where appropriate). For helical and beta-protein models, similar folding pathways were obtained in diamond lattice simulations, using an entirely different set of local Monte Carlo moves. This argues strongly that the results are universal; that is, they are independent of lattice, protein model or the particular realization of Monte Carlo dynamics. Overall, these simulations demonstrate that the folding of all known protein motifs can be achieved in the context of a single class of lattice models that includes realistic backbone structures and idealized side-chains. VL - 221 UR - http://dx.doi.org/10.1016/0022-2836(91)80070-B ER - TY - JOUR T1 - Monte Carlo dynamics study of motions in cis-unsaturated hydrocarbon chains JF - The Journal of Chemical Physics Y1 - 1991 A1 - Yehudi K. Levine A1 - Jeffrey Skolnick A1 - Andrzej Koliński KW - Bilayers KW - Chains KW - Chemical Bonds KW - Hydrocarbons KW - Hydrogen Bonds KW - Lipids KW - Molecular Motion KW - Monte Carlo Method KW - Temperature Effects AB - A Monte Carlo dynamics study of the motions of hydrocarbon chains containing cis double bonds is presented. The simulations utilize the high‐coordination {2 1 0} lattice for the simultaneous representation of the tetrahedrally bonded carbon atoms and the planar unsaturated segment. Results on single chains undergoing free motion in space and tethered to an impenetrable planar interface are reported. The introduction of a cis double bond into a hydrocarbon chain induces a slowdown in the dynamics. The simulations show this to be a universal result independent of the representation of the chain on the lattice. In contrast, polyunsaturated chains are found to be more mobile than saturated ones. VL - 95 UR - http://smartech.gatech.edu/handle/1853/26899 ER - TY - JOUR T1 - Prediction of protein secondary structure by an enhanced neural network JF - Acta Biochimica Polonica Y1 - 1991 A1 - Michał Vieth A1 - Andrzej Koliński AB - Computational model of neural network is used for prediction of secondary structure of globular proteins of known sequence. In contrast to earlier works some information about expected tertiary interactions were built in into the neural network. As a result the prediction accuracy was improved by 3% to 5%. Possible applications of this new approach are briefly discussed. PB - Polish Biochemical Society VL - 38 ER - TY - JOUR T1 - Solvent effects on nitrogen NMR shieldings in azines JF - Journal of Magnetic Resonance Y1 - 1991 A1 - Michal Witanowski A1 - Wanda Sicinska A1 - S. Biernat A1 - Graham A. Webb AB - The ranges of solvent effects on the nitrogen shielding are reported for pyridine, 1,2-1,3-, and 1,4-diazine, and 1,3,5-triazine. These ranges are both significant and variable from about 48 ppm for 1,2-diazine to about 1 I ppm for the triazine. The former is the largest solvent-induced range so far observed in nitrogen NMR. Contributions to the nitrogen shielding ranges from hydrogen bonding and solvent polarity effects are estimated. The former effect usually provides a dominant contribution and can be associated with the strength of the hydrogen bond formed from the solvent to the solute. The contribution to the change in nitrogen shielding from a change in solvent polarity is also significant but usually less than that due to hydrogen bonding. Both effects operate to produce changes in the nitrogen shielding in the same direction. The polarity effects are unusually large in the case of 1,2-diazine and this is corroborated by INDO/S-SOS shielding calculations using the solvaton model. VL - 91 UR - http://www.sciencedirect.com/science/article/pii/002223649190193W ER - TY - JOUR T1 - Static and dynamic properties of a new lattice model of polypeptide chains JF - The Journal of Chemical Physics Y1 - 1991 A1 - Andrzej Koliński A1 - Mariusz Milik A1 - Jeffrey Skolnick KW - Alanines KW - Chains KW - Glycine KW - Lattice Dynamics KW - Polypeptides KW - Proteins KW - Relaxation Time KW - Self−Diffusion AB - The equilibrium and dynamic properties of a new lattice model of proteins are explored in the athermal limit. In this model, consecutive α‐carbons of the model polypeptide are connected by vectors of the type (±2,±1,0). In all cases, the chains have a finite backbone thickness which is close to that present in real proteins. Three different polypeptides are examined: polyglycine, polyalanine, and polyleucine. In the latter two cases, the side chains (whose conformations are extracted from known protein crystal structures) are included. For the equilibrium chain dimensions, with increasing side chain bulkiness, the effective chain length is smaller. The calculations suggest that these model polypeptides are in the same universality class as other polymer models. One surprising result is that although polyalanine and polyleucine have chiral sidechains, they do not induce a corresponding handedness of the main chain. For both polyleucine and polyalanine, the scaling of the self‐diffusion constant and the terminal relaxation time are consistent with Rouse dynamics of excluded volume chains. Polyglycine exhibits a slightly stronger chain length dependence for these properties. This results from a finite length effect due to moderately long lived, local self‐entanglements arising from the thin effective cross section of the chain backbone. VL - 94 UR - http://link.aip.org/link/JCPSA6/v94/i5/p3978/s1&Agg=doi ER - TY - JOUR T1 - Dynamic Monte Carlo Globular Protein Folding and Structure JF - Chemical Design Automation News Y1 - 1990 A1 - Jeffrey Skolnick A1 - Andrzej Koliński A1 - Andrzej Sikorski VL - 5 ER - TY - JOUR T1 - Dynamic Monte Carlo Simulations of Globular Protein Folding, Structure and Dynamics JF - Comments on Molecular & Cell Biology Y1 - 1990 A1 - Jeffrey Skolnick A1 - Andrzej Koliński A1 - Andrzej Sikorski VL - 6 ER - TY - JOUR T1 - Dynamic Monte Carlo simulations of globular protein folding/unfolding pathways: I. Six-member, Greek Key beta-Barrel proteins JF - Journal of Molecular Biology Y1 - 1990 A1 - Jeffrey Skolnick A1 - Andrzej Koliński AB - In the context of a simplified diamond lattice model of a six-member, Greek key beta-barrel protein that is closely related in topology to plastocyanin, the nature of the folding and unfolding pathways have been investigated using dynamic Monte Carlo techniques. The mechanism of Greek key assembly is best described as punctuated "on site construction". Folding typically starts at or near a beta-turn, and then the beta-strands sequentially form by using existing folded structure as a scaffold onto which subsequent tertiary structure assembles. On average, beta-strands tend to zip up from one tight bend to the next. After the four-member, beta-barrel assembles, there is a long pause as the random coil portion of the chain containing the long loop thrahes about trying to find the native state. Thus, there is an entropic barrier that must be surmounted. However, while a given piece of the protein may be folding, another section may be unfolding. A competition therefore exists to assemble a fairly stable intermediate before it dissolves. Folding may initiate at any of the tight turns, but the turn closer to the N terminus seems to be preferred due to well-known excluded volume effects. When the protein first starts to fold, there are a multiplicity of folding pathways, but the number of options is reduced as the system gets closer to the native state. In the early stages, the excluded volume effect exerted by the already assembled protein helps subsequent assembly. Then, near the native conformation, the folded parts reduce the accessible conformational space available to the remaining unfolded sections. Unfolding essentially occurs in reverse. Employing a simple statistical mechanical theory, the configurational free energy along the reaction co-ordinate for this model has been constructed. The free energy surface, in agreement with the simulations, provides the following predictions. The transition state is quite near the native state, and consists of five of the six beta-strands being fully assembled, with the remaining long loop plus sixth beta-strand in place, but only partially assembled. It is separated from the beta-barrel intermediate by a free energy barrier of mainly entropic origin and from the native state by a barrier that is primarily energetic in origin. The latter feature is in agreement with the "Cardboard Box" model described by Goldenberg and Creighton but, unlike their model, the transition state is not a high-energy distorted form of the native state. VL - 212 UR - http://www.sciencedirect.com/science/article/pii/002228369090238H ER - TY - CHAP T1 - Dynamics of dense polymer systems: Computer simulations and analytic theories T2 - Advances in Chemical Physics Y1 - 1990 A1 - Jeffrey Skolnick A1 - Andrzej Koliński KW - Brownian dynamics KW - Monte Carlo results KW - relaxation times KW - Rouse model KW - unknotted rings JF - Advances in Chemical Physics VL - 77 UR - http://books.google.com/books?hl=en&lr=&id=D6Ve3CgALtkC&oi=fnd&pg=PA223&dq=Dynamics+of+dense+polymer+systems:+computer+simulations+and+analytic+theories&ots=19NoqLh3qY&sig=ONsS49-adBsoKzx\_8nplUSmOIMI ER - TY - JOUR T1 - Monte Carlo dynamics of a dense system of chain molecules constrained to lie near an interface. A simplified membrane model JF - The Journal of Chemical Physics Y1 - 1990 A1 - Mariusz Milik A1 - Andrzej Koliński A1 - Jeffrey Skolnick KW - Bilayers KW - Chains KW - Constraints KW - Density KW - Interface Phenomena KW - Lipids KW - Liquid Structure KW - Membranes KW - Monte Carlo Method KW - Order Parameters KW - Orientation AB - The static and dynamic properties of a dense system of flexible lattice chain molecules, one of whose ends is constrained to lie near an impenetrable interface, have been studied by means of the dynamic Monte Carlo method. It is found that increasing the surface density of the chains in the layer increases the orientational order. The value of the order parameter of the chain segments decreases with increasing distance from the interace. The short time dynamics of the model chains are similar to those observed in polymer melts. Then, there is a time regime of strongly hindered collective motion at intermediate distance scales. Finally, for distances greater than the chain dimensions, free lateral diffusion of the chains is recovered. It is shown that the model exhibits many features of the real systems such as detergents on a surface and lipid bilayers. VL - 93 UR - http://link.aip.org/link/JCPSA6/v93/i6/p4440/s1 ER - TY - JOUR T1 - Simulations of the folding of a globular protein JF - Science Y1 - 1990 A1 - Jeffrey Skolnick A1 - Andrzej Koliński AB - Dynamic Monte Carlo simulations of the folding of a globular protein, apoplastocyanin, have been undertaken in the context of a new lattice model of proteins that includes both side chains and a-carbon backbone atoms and that can approximate native conformations at the level of 2 angstroms (root mean square) or better. Starting from random-coil unfolded states, the model apoplastocyanin was folded to a native conformation that is topologically similar to the real protein. The present simulations used a marginal propensity for local secondary structure consistent with but by no means enforcing the native conformation and a full hydrophobicity scale in which any nonbonded pair of side chains could interact. These molecules folded through a punctuated on-site mechanism of assembly where folding initiated at or near one of the turns ultimately found in the native conformation. Thus these simulations represent a partial solution to the globular-protein folding problem. VL - 250 UR - http://cssb.biology.gatech.edu/skolnick/publications/pdffiles/087.pdf ER - TY - JOUR T1 - Study of solvent effects on the nitrogen NMR shieldings of some indolizines JF - Magnetic Resonance in Chemistry Y1 - 1990 A1 - Michal Witanowski A1 - Wanda Sicinska A1 - Zbigniew Grabowski A1 - Graham A. Webb KW - Indolizines KW - Nitrogen Shieldings KW - Solvent effects AB - Solvent effects on the nitrogen NMR shieldings of indolizine and three azaindolizines are presented for a range of thirteen solvents. The results are discussed in terms of hydrogen-bonding an solvent polarity effects. ‘Pyridine-type’ nitrogen atoms show a much larger range of solvent effects than do ‘pyrrole-type’ nitrogens; solvent to solute hydrogen bonding is the dominant contribution to the changes in shielding for the ‘pyridine-type’ nitrogen atoms as the solvent is varied. Solvent polarity effects are important for both types of nitrogen atom in azaindolizines and can be attributed to a solvent-induced electronic charge separation between the nitrogen atoms concerned.Quantum chemical calculations involving the solvaton model are used to provide supporting evidence for the importance of solvent polarity effects on nitrogen shieldings in azaindolizines. PB - John Wiley & Sons, Ltd. VL - 28 UR - http://dx.doi.org/10.1002/mrc.1260281114 ER - TY - JOUR T1 - 14N NMR nuclear shielding and the electronic structure of dibenzo[1,3a,4,6a]tetrazapentalene JF - Magnetic Resonance in Chemistry Y1 - 1989 A1 - Michal Witanowski A1 - J. Sitkowski A1 - Wanda Sicinska A1 - S. Biernat A1 - Graham A. Webb KW - 14N NMR KW - Charge separation KW - N-Heterocycles KW - Nuclear shielding calculations AB - 14N NMR data and semiempirical molecular orbital calculations are reported for dibenzo-[1,3a,4,6a]tetrazapentalene (1). The 14N signals were assigned by means of the results of the molecular orbital calculations and measured relative signal widths. A comparison was made with results for some azolopyridines. A linear correlation was obtained between the nitrogen shieldings, expressed with respect to the bridging nitrogen atom, and the corresponding relative charge densities. Thus nitrogen nuclear shielding results provide a good estimation of electron charge distribution in these molecules. Compound 1 provides the first case in which the shielding of a pyridine-type nitrogen atom is greater than that of the indolizine-type nitrogen. PB - John Wiley & Sons, Ltd. VL - 27 UR - http://dx.doi.org/10.1002/mrc.1260270116 ER - TY - JOUR T1 - Assignments of nitrogen NMR shieldings in azine heterocycles by means of a self-adjusting linear system of incremens JF - International Journal of Spectroscopy Y1 - 1989 A1 - Michal Witanowski A1 - Wanda Sicinska A1 - S. Biernat VL - 7 ER - TY - JOUR T1 - Combinatorial Entropy of Dense Systems of n-mers. The Effect of Shape Studied by Monte Carlo Method JF - Acta Physica Polonica Y1 - 1989 A1 - Andrzej Koliński A1 - Krzysztof Kurcinski A1 - Andrzej Orszagh VL - 75 ER - TY - JOUR T1 - Computer simulations of globular protein folding and tertiary structure JF - Annual Review of Physical Chemistry Y1 - 1989 A1 - Jeffrey Skolnick A1 - Andrzej Koliński AB - In summary, although a large number of disparate techniques have been applied to predict the tertiary structure of globular proteins from their amino acid sequence, the solution is not yet at hand. Methodologies for predicting the conformation of constrained, small protein fragments appear to be successful. As the size of the system increases, the level of detail of the treatment decreases; approaches that employ very detailed potentials appear to be limited to about 30-40 residues. Although this is a major advance, methods that reduce the effective number of degrees of freedom are clearly required. Lattice representations coupled to highly efficient Monte Carlo procedures appear to be one such approach. Thus, although a number of theoretical advances in the computer simulation of globular protein structure have been made, much work remains to be done before the globular protein folding problem is solved. VL - 40 UR - http://www.annualreviews.org/doi/abs/10.1146/annurev.pc.40.100189.001231 ER - TY - JOUR T1 - Dynamic Monte Carlo Simulation of a melt of ring polymers JF - Polymer Preprints Y1 - 1989 A1 - Jeffrey Skolnick A1 - Andrzej Koliński A1 - Andrzej Sikorski A1 - Robert Yaris VL - 30 ER - TY - JOUR T1 - Dynamic Monte Carlo study of the folding of a six-stranded Greek key globular protein JF - Proceedings of the National Academy of Sciences of the United States of America Y1 - 1989 A1 - Jeffrey Skolnick A1 - Andrzej Koliński A1 - Robert Yaris KW - all-or-none transition KW - multiple domain protein KW - plastocyanin model AB - To help elucidate the general rules of equilibrium globular protein folding, dynamic Monte Carlo simulations of a model beta-barrel globular protein having the six-stranded Greek key motif characteristic of real globular proteins were undertaken. The model protein possesses a typical beta-barrel amino acid sequence; however, all residues of a given type (e.g. hydrophobic residues) are identical. Even in the absence of site-specific interactions, starting from a high-temperature denatured state, these models undergo an all-or-none transition to a structurally unique six-stranded beta-barrel. These simulations suggest that the general rules of globular protein folding are rather robust in that the overall tertiary structure is determined by the general pattern of hydrophobic, hydrophilic, and turn-type residues, with site-specific interactions mainly involved in structural fine tuning of a given topology. Finally, these studies suggest that loops may play an important role in producing a unique native state. Depending on the stability of the native conformation of the long loop in the Greek key, the conformational transition can be described by a two-state, three-state, or even larger number of multiple equilibrium states model. VL - 86 UR - http://www.pnas.org/content/86/4/1229.long ER - TY - JOUR T1 - Effects of solute–solvent interactions on the nitrogen nuclear shieldings of some alkyl cyanides JF - Magnetic Resonance in Chemistry Y1 - 1989 A1 - Michal Witanowski A1 - Wanda Sicinska A1 - Graham A. Webb KW - Alkyl cyanides KW - Nitrogen nuclear shieldings KW - Solute-solvent interactions AB - It was found that the range of solvent effects on the nitrogen NMR shielding of the cyano group appears to be almost independent of the nature of the attached alkyl group and to be in excess of 20 ppm. Effects due to both the polarity of the medium and hydrogen bonding are observed to contribute almost equally to the nitrogen shielding ranges measured for four alkyl cyanides. These contributions are determined from the shielding in nitrogen variations with the solvent by means of a four-parameter model and are supported by molecular orbital calculations employing the solvaton description of non-specific solute-solvent interactions. The observed responses of the nitrogen shieldings to solvent effect are found to be significantly different from those reported for sp2-type nitrogen atoms. PB - John Wiley & Sons, Ltd. VL - 27 UR - http://dx.doi.org/10.1002/mrc.1260270415 ER - TY - JOUR T1 - Monte Carlo studies on equilibrium globular protein folding. II. Beta-barrel globular protein models JF - Biopolymers Y1 - 1989 A1 - Jeffrey Skolnick A1 - Andrzej Koliński A1 - Robert Yaris KW - Algorithms KW - Models KW - Monte Carlo Method KW - Protein Conformation KW - Proteins KW - Theoretical AB - In the context of dynamic Monte Carlo simulations on a model protein confined to a tetrahedral lattice, the interplay of protein size and tertiary structure, and the requirements for an all-or-none transition to a unique native state, are investigated. Small model proteins having a primary sequence consisting of a central bend neutral region flanked by two tails having an alternating hydrophobic/hydrophilic pattern of residues are seen to undergo a continuous transition to a beta-hairpin collapsed state. On increasing the length of the tails, the beta-hairpin structural motif is found to be in equilibrium with a four-member beta-barrel. Further increase of the tail length results in the shift of the structural equilibrium to the four-member beta-barrel. The random coil to beta-barrel transition is of an all-or-none character, but while the central turn is always the desired native bend, the location of the turns involving the two external strands is variable. That is, beta-barrels having the external stands that are two residues out of register are also observed in the transition region. Introduction into the primary sequence of two additional regions that are at the very least neutral toward turn formation produces an all-or-none transition to the unique, native, four-member beta-barrel. Various factors that can augment the stability of the native conformation are explored. Overall, these folding simulations strongly indicate that the general rules of globular protein folding are rather robust–namely, one requires a general pattern of hydrophobic/hydrophilic residues that allow the protein to have a well-defined interior and exterior and the presence of regions in the amino acid sequence that at the very least are locally indifferent to turn formation. Since no site-specific interactions between hydrophobic and hydrophilic residues are required to produce a unique four-member beta-barrel, these simulations strongly suggest that site specificity is involved in structural fine-tuning. VL - 28 UR - http://www.ncbi.nlm.nih.gov/pubmed/2730942 ER - TY - JOUR T1 - A NMR study of solute-solvent interactions as a function of the nitrogen shielding of pyridine N-oxide JF - Journal of Magnetic Resonance Y1 - 1989 A1 - Michal Witanowski A1 - Wanda Sicinska A1 - S. Biernat A1 - Graham A. Webb AB - The range of solvent effects on the nitrogen shielding of pyridine N-oxide is found to be comparable to that of pyridine, amounting to about 30 ppm. The largest contribution to this range arises from hydrogen bonding from the solvents to the oxygen atom of pyridine N-oxide. For the first time it is demonstrated that hydrogen bonding to a neighboring atom can have a comparable effect on nitrogen shielding as would direct hydrogen bonding to the nitrogen atom. Medium polarity effects on the nitrogen shielding of pyridine and its N-oxide are of the same sign and order of magnitude. This is corroborated by INDO/S-SOS shielding calculations using the solvaton model. These medium polarity effects amount to a nitrogen shielding variation not exceeding 6 ppm while those due to hydrogen bonding exceed 20 ppm. VL - 83 UR - http://www.sciencedirect.com/science/article/pii/0022236489901960 ER - TY - JOUR T1 - Phenomenological Theory of Polymer Melt Dynamics JF - International Journal of Modern Physics B Y1 - 1989 A1 - Jeffrey Skolnick A1 - Robert Yaris A1 - Andrzej Koliński AB - A particularly interesting problem in polymer physics is the mechanism by which an individual polymer chain moves in a polymer melt or concentrated polymer solution. The first rather successful model of polymer dynamics was the reptation model of de Gennes which asserts that due to the effect of entanglements a polymer finds itself confined to a tube. Thus, the dominant long wavelength motion of the chain should be slithering out the ends of the tube. In order to examine the validity of the reptation model, a series of dynamic Monte Carlo simulations were performed. Although the simulations are on chains sufficiently long that agreement with the experimentally observed scaling with degree of polymerization n of the self diffusion constant and terminal relaxation time is observed, reptation does not appear to be the dominant mechanism of long distance motion. Rather the motion is isotropic, with the slowdown from dilute solution behavior arising from the formation of dynamic entanglements — rare long lived contacts where a given chain drags another chain through the melt for times on the order of longest internal relaxation time. Motivated by the simulations results, a phenomenological theory for the diffusive and viscoelastic behavior is developed that is consistent with both simulations and experiment and which does not invoke reptation. The major conclusions arising from the theoretical approach are described, and comparison is made with experiment. VL - 3 IS - 01 ER - TY - JOUR T1 - Solvent polarity and hydrogen bonding effects on the nitrogen NMR shielding of nitromethane JF - International Journal of Spectroscopy Y1 - 1989 A1 - Michal Witanowski A1 - Wanda Sicinska A1 - S. Biernat VL - 7 ER - TY - JOUR T1 - Monte Carlo simulations of the folding of beta-barrel globular proteins JF - Proceedings of the National Academy of Sciences of the United States of America Y1 - 1988 A1 - Jeffrey Skolnick A1 - Andrzej Koliński A1 - Robert Yaris AB - With the use of dynamic Monte Carlo simulations, the necessary conditions for the collapse from a random-coil denatured state to a structurally unique four-member beta-barrel native state of a model globular protein have been investigated. These systems are free to roam through all of configuration space--both native and nonnative interactions are allowed. The relative importance of hydrophobic and hydrophilic interactions and the presence or absence of statistical bend-forming regions for the formation of a unique native state are examined, and the conditions necessary for a denatured-to-native (and vice versa) conformational transition that is thermodynamically all-or-none and which always results in collapse to the same, four-member beta-barrel are explored. These conditions are found to be a general pattern of hydrophobic/hydrophilic residues that allows the native state to differentiate the interior from the exterior of the protein and the presence of regions that are, at the very least, neutral toward turn formation. The former set of interactions seems to define the mean length of the beta-stretch, and the latter set serves to lock the native state into the lowest free energy state, the native conformation. These folding simulations strongly suggest that the general rules of protein folding are rather robust and that site-specific tertiary interactions are only involved in structural fine tuning. The conditions required for the formation of a structurally unique native state from a manifold of collapsed conformations that are originally quite close in energy is highly suggestive of a mechanism of protein evolution by means of random mutations. The implications of these folding studies for such a mechanism are qualitatively explored. VL - 85 UR - http://www.pnas.org/content/85/14/5057.short ER - TY - JOUR T1 - Phenomenological theory of the dynamics of polymer melts. I. Analytic treatment of self-diffusion JF - The Journal of Chemical Physics Y1 - 1988 A1 - Jeffrey Skolnick A1 - Robert Yaris A1 - Andrzej Koliński AB - In the context of dynamic Monte Carlo (MC) simulations on dense collections of polymer chains confined to a cubic lattice, the nature of the dynamic entanglements giving rise to the degree of polymerization n, dependence of the self-diffusion constant D~n[superscript −2] is examined. Consistent with our previous simulation results, which failed to find evidence for reptation as the dominant mechanism of polymer melt motion [J. Chem. Phys. 86, 1567, 7164, 7174 (1987)], long-lived dynamic entanglement contacts between pairs of segments belonging to different chains are extremely rare and are mobile with respect to the laboratory fixed frame. It is suggested that dynamic entanglements involve the dragging of one chain by another through the melt for times on the order of the terminal relaxation time of the end-to-end vector. Employing the physical description provided by the MC simulation, the general expression of Hess [Macromolecules 19, 1395 (1986)] for the friction constant increment experienced by a polymer due to the other polymers forms the basis of a phenomenological derivation of D~n[superscript −2] for monodisperse melts that does not require the existence of reptation. Rather, such behavior is dependent on the relatively benign assumptions that the long distance global motions of the chains are uncorrelated, that the dynamic contacts can be truncated at the pair level, and that the propagator describing the evolution between dynamic contacts contains a free Rouse chain component. The mean distance between dynamic entanglements is predicted to depend inversely on concentration, in agreement with experiment. Moreover, as the free Rouse component is frozen out, for chains greater than an entanglement length ne, a molecular weight independent glass transition is predicted. Extension to bidisperse melts predicts that the probe diffusion coefficient Dp depends on the matrix degree of polymerization, nm, as n. Finally, comparison is made between the theoretical expressions and MC results for mono- and bidisperse melts VL - 3 UR - http://link.aip.org/link/JCPSA6/v88/i2/p1407/s1 ER - TY - JOUR T1 - Conformation studies of some sulphurdiimides by spectroscopic techniques JF - Journal of Molecular Structure Y1 - 1987 A1 - Wanda Sicinska A1 - L. Stefaniak A1 - Michal Witanowski A1 - Graham A. Webb AB - 1H, 13C, 14N and 15N data are reported for some diphenylsulphurdiimides, as well as some electronic spectroscopic results. The 1H NMR spectra lead to the identification of symmetric and unsymmetric forms, whose relative amounts are determined by integration at various temperatures. For the first time both forms are observed in the electronic spectra and assignments are given. True ϵo values are reported and the question of molecular planarity discussed. VL - 158 UR - http://www.sciencedirect.com/science/article/pii/0022286087800042 ER - TY - JOUR T1 - Conformational analysis of some thionitrites JF - Journal of Molecular Structure Y1 - 1987 A1 - Wanda Sicinska A1 - L. Stefaniak A1 - Michal Witanowski A1 - Graham A. Webb VL - 160 UR - http://www.sciencedirect.com/science/article/pii/0022286087870151 ER - TY - JOUR T1 - Does reptation describe the dynamics of entangled, finite length polymer systems? A model simulation JF - The Journal of Chemical Physics Y1 - 1987 A1 - Andrzej Koliński A1 - Jeffrey Skolnick A1 - Robert Yaris KW - Chains KW - Computerized Simulation KW - dynamics KW - Monte Carlo Method KW - Polymers AB - In order to examine the validity of the reptation model of motion in a dense collection of polymers, dynamic Monte Carlo (MC) simulations of polymer chains composed of n beads confined to a diamond lattice were undertaken as a function of polymer concentration ϕ and degree of polymerization n. We demonstrate that over a wide density range these systems exhibit the experimentally required molecular weight dependence of the center‐of‐mass self‐diffusion coefficient D∼n−2.1 and the terminal relaxation time of the end‐to‐end vector τR∼n3.4. Thus, these systems should represent a highly entangled collection of polymers appropriate to look for the existence of reptation. The time dependence of the average single bead mean‐square displacement, as well as the dependence of the single bead displacement on position in the chain were examined, along with the time dependence of the center‐of‐mass displacement. Furthermore, to determine where in fact a well‐defined tube exists, the mean‐square displacements of a polymer chain down and perpendicular to its primitive path defined at zero time were calculated, and snapshots of the primitive path as a function of time are presented. For an environment where all the chains move, no evidence of a tube, whose existence is central to the validity of the reptation model, was found. However, if a single chain is allowed to move in a partially frozen matrix of chains (where all chains but one are pinned every ne beads, and where between pin points the other chains are free to move), reptation with tube leakage is recovered for the single mobile chain. The dynamics of these chains possesses aspects of Rouse‐like motion; however, unlike a Rouse chain, these chains undergo highly cooperative motion that appears to involve a backflow between chains to conserve constant average density. While these simulations cannot preclude the onset of reptation at higher molecular weight, they strongly argue at a minimum for the existence with increasing n of a crossover regime from simple Rouse dynamics in which reptation plays a minor role at best. VL - 86 UR - http://link.aip.org/link/JCPSA6/v86/i3/p1567/s1 ER - TY - JOUR T1 - Dynamic Monte Carlo study of the conformational properties of long flexible polymers JF - Macromolecules Y1 - 1987 A1 - Andrzej Koliński A1 - Jeffrey Skolnick A1 - Robert Yaris VL - 20 UR - http://pubs.acs.org/doi/abs/10.1021/ma00168a039 ER - TY - JOUR T1 - Monte Carlo studies of the long-time dynamics of dense polymer systems. The failure of the reptation model JF - Accounts of Chemical Research Y1 - 1987 A1 - Jeffrey Skolnick A1 - Andrzej Koliński A1 - Robert Yaris VL - 20 UR - http://pubs.acs.org/doi/abs/10.1021/ar00141a006 ER - TY - JOUR T1 - Monte Carlo studies on equilibrium globular protein folding. I. Homopolymeric lattice models of beta-barrel proteins JF - Biopolymers Y1 - 1987 A1 - Andrzej Koliński A1 - Jeffrey Skolnick A1 - Robert Yaris KW - Biological KW - Models KW - Monte Carlo Method KW - Protein Conformation KW - Proteins AB - Dynamic Monte Carlo studies have been performed on various diamond lattice models of β-proteins. Unlike previous work, no bias toward the native state is introduced; instead, the protein is allowed to freely hunt through all of phase space to find the equilibrium conformation. Thus, these systems may aid in the elucidation of the rules governing protein folding from a given primary sequence; in particular, the interplay of short- vs long-range interaction can be explored. Three distinct models (A[BOND]C) were examined. In model A, in addition to the preference for trans (t) over gauche states (g+ and g−) (thereby perhaps favoring β-sheet formation), attractive interactions are allowed between all nonbonded, nearest neighbor pairs of segments. If the molecules possess a relatively large fraction of t states in the denatured form, on cooling spontaneous collapse to a well-defined β-barrel is observed. Unfortunately, in model A the denatured state exhibits too much secondary structure to correctly model the globular protein collapse transition. Thus in models B and C, the local stiffness is reduced. In model B, in the absence of long-range interactions, t and g states are equally weighted, and cooperativity is introduced by favoring formation of adjacent pairs of nonbonded (but not necessarily parallel) t states. While the denatured state of these systems behaves like a random coil, their native globular structure is poorly defined. Model C retains the cooperativity of model B but allows for a slight preference of t over g states in the short-range interactions. Here, the denatured state is indistinguishable from a random coil, and the globular state is a well-defined β-barrel. Over a range of chain lengths, the collapse is well represented by an all-or-none model. Hence, model C possesses the essential qualitative features observed in real globular proteins. These studies strongly suggest that the uniqueness of the globular conformation requires some residual secondary structure to be present in the denatured state. VL - 26 UR - http://www.ncbi.nlm.nih.gov/pubmed/3607251 ER - TY - JOUR T1 - Monte Carlo studies on the long time dynamic properties of dense cubic lattice multichain systems. II. Probe polymer in a matrix of different degrees of polymerization JF - The Journal of Chemical Physics Y1 - 1987 A1 - Andrzej Koliński A1 - Jeffrey Skolnick A1 - Robert Yaris KW - Chains KW - Computerized Simulation KW - dynamics KW - Liquid Structure KW - Matrix Isolation KW - Melts KW - Monte Carlo Method KW - Polymerization KW - Polymers AB - The dynamics of a probe chain consisting of nP =100 segments in a matrix of chains of length of nM=50 up to nM=800 at a total volume fraction of polymer ϕ=0.5 have been simulated by means of cubic lattice Monte Carlo dynamics. The diffusion coefficient of the probe chain over the range of nM under consideration decreases by about 30%, a behavior rather similar to that seen in real melts of very long chains. Furthermore, the analysis of the probe chain motion shows that the mechanism of motion is not reptation‐like and that the cage effect of the matrix is negligible. That is, the local fluctuations of the topological constraints imposed by the long matrix chains (even for nM=800) are sufficiently large to provide for essentially isotropic, but somewhat slowed down, motion of the probe, nP =100, chains relative to the homopolymer melt. The results of these MC experiments are discussed in the context of theoretical predictions and experimental findings for related systems. VL - 86 UR - http://link.aip.org/link/JCPSA6/v86/i12/p7174/s1 ER - TY - JOUR T1 - Monte Carlo studies on the long time dynamic properties of dense cubic lattice multichain systems. I. The homopolymeric melt JF - The Journal of Chemical Physics Y1 - 1987 A1 - Andrzej Koliński A1 - Jeffrey Skolnick A1 - Robert Yaris KW - Chains KW - Computerized Simulation KW - dynamics KW - Liquid Structure KW - Melts KW - Monte Carlo Method KW - Polymers AB - Dynamic Monte Carlo simulations of long chains confined to a cubic lattice system at a polymer volume fraction of ϕ=0.5 were employed to investigate the dynamics of polymer melts. It is shown that in the range of chain lengths n, from n=64 to n=800 there is a crossover from a weaker dependence of the diffusion coefficient on chain length to a much stronger one, consistent with D∼n−2. Since the n−2 scaling relation signals the onset of highly constrained dynamics, an analysis of the character of the chain contour motion was performed. We found no evidence for the well‐defined tube required by the reptation model of polymer melt dynamics. The lateral motions of the chain contour are still large even in the case when n=800, and the motion of the chain is essentially isotropic in the local coordinates. Hence, the crossover to the D∼n−2 regime with increasing chain length of this monodisperse model melt is not accompanied by the onset of reptation dynamics. VL - 86 UR - http://link.aip.org/link/JCPSA6/v86/i12/p7164/s1 ER - TY - JOUR T1 - The collapse transition of semiflexible polymers. A Monte Carlo simulation of a model system JF - The Journal of Chemical Physics Y1 - 1986 A1 - Andrzej Koliński A1 - Jeffrey Skolnick A1 - Robert Yaris KW - Chains KW - Computerized Simulation KW - Conformational Changes KW - Diamond Lattices KW - Flexibility KW - Mathematical Models KW - Molecular Structure KW - Monte Carlo Method KW - Polymers AB - Monte Carlo simulations have been performed on a diamond lattice model of semiflexible polymers for a range of flexibilities and a range of chain lengths from 50 to 800 segments. The model includes both repulsive (excluded volume) and attractive segment–segment interactions. It is shown that the polymers group into two classes, ‘‘flexible’’ and ‘‘stiff.’’ The flexible polymers exhibit decreasing chain dimensions as the temperature decreases with a gradual collapse from a loose random coil, high temperature state to a dense random coil, low temperature state. The stiffer polymers, on the other hand, exhibit increasing chain dimensions with decreasing temperature until at a critical temperature there is a sudden collapse to an ordered high density, low temperature state. This difference is due to the relative strength of the segment–segment attractive interactions compared to the energetic preference for a trans conformational state over a gauche state. When the attractive interaction is relatively strong (flexible case) the polymer starts to collapse before rotational degrees of freedom freeze out, leading to a disordered dense state. When the attractive interaction is relatively weak (stiff case) the polymer starts to freeze out rotational degrees of freedom before it finally collapses to a highly ordered dense state. VL - 85 UR - http://link.aip.org/link/JCPSA6/v85/i6/p3585/s1 ER - TY - Generic T1 - Monte Carlo dynamics of diamond-lattice multichain systems T2 - AIP Conference Proceedings Y1 - 1986 A1 - Andrzej Koliński A1 - Jeffrey Skolnick A1 - Robert Yaris JF - AIP Conference Proceedings VL - 137 UR - http://smartech.gatech.edu/handle/1853/27919 ER - TY - JOUR T1 - Monte Carlo simulations on an equilibrium globular protein folding model JF - Proceedings of the National Academy of Sciences of the United States of America Y1 - 1986 A1 - Andrzej Koliński A1 - Jeffrey Skolnick A1 - Robert Yaris KW - Models KW - Protein Conformation KW - Statistics as Topic KW - Structural KW - Structure-Activity Relationship KW - Temperature KW - Thermodynamics AB -

Monte Carlo simulations were performed on a diamond lattice, globular protein model in which the trans conformational state is energetically favored over the gauche states (thereby perhaps favoring a beta-sheet secondary structure) and in which nonspecific nonbonded nearest-neighbor attractive interactions are allowed. If the attractive interactions are sufficiently weak that the molecule possesses a relatively high fraction of trans states in the denatured state, then on collapse, a beta-barrel tertiary structure, highly reminiscent of the "native" structure seen in beta-proteins, spontaneously forms. If, however, the attractive interactions are dominant, a coil-to-random globule collapse transition is observed. The roles of short-, medium-, and long-range interactions and topological constraints in determining the observed tertiary structure are addressed, and the implications and limitations of the simulations for the equilibrium folding process in renal globular proteins are explored.

VL - 83 UR - http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=386697&tool=pmcentrez&rendertype=abstract ER - TY - JOUR T1 - Monte Carlo study of local orientational order in a semiflexible polymer melt model JF - Macromolecules Y1 - 1986 A1 - Andrzej Koliński A1 - Jeffrey Skolnick A1 - Robert Yaris VL - 19 UR - http://pubs.acs.org/doi/abs/10.1021/ma00164a017 ER - TY - JOUR T1 - Order-Disorder Transitions in Tetrahedral Lattice Polymer Systems JF - Macromolecules Y1 - 1986 A1 - Andrzej Koliński A1 - Jeffrey Skolnick A1 - Robert Yaris VL - 19 ER - TY - JOUR T1 - On the short time dynamics of dense polymeric systems and the origin of the glass transition: A model system JF - The Journal of chemical physics Y1 - 1986 A1 - Andrzej Koliński A1 - Jeffrey Skolnick A1 - Robert Yaris VL - 84 UR - http://link.aip.org/link/JCPSA6/v84/i3/p1922/s1 ER - TY - JOUR T1 - Some properties of rigid cores with flexible tails. Monte carlo simulation of two-dimensional lattice systems JF - Chemical Physics Letters Y1 - 1985 A1 - Andrzej Koliński AB - The combinatorial entropy of two-dimensional triangular lattice systems consisting of rigid cores with flexible tails was calculated by means of the Monte Carlo method. Large differences between the mean-field prediction and Monte Carlo data were observed. Systems of molecules with sufficiently long core undergo a first-order phase transition at high density. VL - 116 UR - http://www.sciencedirect.com/science/article/pii/0009261485801469 ER - TY - JOUR T1 - A 15N NMR study of some sulphilimines and sulphone imines JF - Bulletin of the Polish Academy of Sciences Y1 - 1984 A1 - Wanda Sicinska A1 - L. Stefaniak A1 - Michal Witanowski A1 - Graham A. Webb VL - 32 ER - TY - JOUR T1 - On the entropy of the multichain athermal lattice systems JF - Journal of Polymer Science: Polymer Letters Edition Y1 - 1984 A1 - Andrzej Koliński PB - John Wiley & Sons, Inc. VL - 22 UR - http://dx.doi.org/10.1002/pol.1984.130220706 ER - TY - JOUR T1 - Monte carlo study of star-branched polymers on the tetrahedral lattice. II. Statistical thermodynamics of single macromolecules JF - Journal of Polymer Science: Polymer Chemistry Edition Y1 - 1984 A1 - Andrzej Sikorski A1 - Andrzej Koliński AB - The thermodynamical properties of the star-branched polymers on the tetrahedral lattice are studied taking into account nearest-neighbor interactions. The excess free energy and energy and heat capacities are computed for wide ranges of chain lengths, reduced potential ϵ/kT, and number of branches. A significant influence of the degree of branching on long-range interactions in the polymer random coil is observed. The possibilities of phase transitions in both linear and branched systems are discussed on the basis of the Monte Carlo data. PB - John Wiley & Sons, Inc. VL - 22 UR - http://dx.doi.org/10.1002/pol.1984.170220110 ER - TY - JOUR T1 - Monte Carlo study of dynamics of the multichain polymer system on the tetrahedral lattice JF - The Journal of Chemical Physics Y1 - 1983 A1 - Andrzej Koliński A1 - Piotr Romiszowski KW - Chains KW - Computerized Simulation KW - Diffusion KW - dynamics KW - Monte Carlo Method KW - Polymers KW - solutions AB - Diffusion of the chain molecules in the concentrated solutions was studied by means of the computer simulation method. The computations were made for various chain lengths and polymer concentrations. It was observed that the rate of diffusion of the polymer chains strongly depends on the chain length according to the relation D∝n−b. It was found that the value of exponent b increases with the polymer concentration. PB - AIP VL - 79 UR - http://link.aip.org/link/?JCP/79/1523/1 ER - TY - JOUR T1 - Monte carlo calculations of the ⊝ point of star-branched macromolecules on tetrahedral lattice JF - Journal of Polymer Science: Polymer Letters Edition Y1 - 1982 A1 - Andrzej Koliński A1 - Andrzej Sikorski PB - John Wiley & Sons, Inc. VL - 20 UR - http://dx.doi.org/10.1002/pol.1982.130200306 ER - TY - JOUR T1 - Monte Carlo Simulation of Radiation-Induced Solid State Polymerization JF - Polymer Y1 - 1982 A1 - Piotr Romiszowski A1 - Andrzej Koliński AB - This report is a continuation of former papers on the computer simulation of solid state polymerization processes using Monte Carlo methods. The first paper 1 considered a model of post-polymerization neglecting chain growth during the irradiation. In the second 2, a radiation-induced in-source solid state polymerization model was presented. Both these models were idealized descriptions of real, two-stage polymerization processes. It is the intention of this report to combine the two aforementioned models and examine the results obtained. When considering the process of solid state polymerization initiated by irradiation, two basic stages can be distinguished: (1) Formation of new active centres in the irradiated monomer sample and the simultaneous growth of polymeric chains. (2) Further growth of the chains after removing the sample from the source of radiation (postpolymerization). In both stages, the termination of chain growth occurs by the trapping of the macroradicals in the mass of the polymer. Such a formulation of the problem is the basis of the pseudostochastic model. VL - 23 IS - July ER - TY - JOUR T1 - Monte Carlo study of star-branched polymers on the tetrahedral lattice. I. Conformation of the macromolecule JF - Journal of Polymer Science: Polymer Chemistry Edition Y1 - 1982 A1 - Andrzej Koliński A1 - Andrzej Sikorski AB - The star-branched polymers on the tetrahedral lattice are studied by means of the Monte Carlo method. The influence of solvent quality on the dimensions of the coil is described for both linear and branched polymer systems of different functionality. It has been observed that the ratios of gyration radii 〈S2〉b/〈S2〉l are greater than those predicted theoretically for the random-flight model. The fourth reduced moment of S2 distribution and the mean-square separation of the branch ends from the center of gravity have been also computed. The changes in segment arrangement in the coil with increasing number of branches have been observed. PB - John Wiley & Sons, Inc. VL - 20 UR - http://dx.doi.org/10.1002/pol.1982.170201110 ER - TY - JOUR T1 - Water Contents and Calculation of Equilibrium Constraints in Benzene Phase on System Water - Benzene - (-OH, -COOH, -NH2, -NO2, -C1) Benzene Derivative JF - Polish Journal of Chemistry Y1 - 1982 A1 - Wiktor Pawlowski A1 - Andrzej Koliński VL - 56 ER - TY - JOUR T1 - 14N NMR studies on some N-sulphinylamines JF - Organic Magnetic Resonance Y1 - 1981 A1 - Wanda Sicinska A1 - L. Stefaniak A1 - Michal Witanowski A1 - Graham A. Webb AB - High precision 14N nuclear screening data are presented for some alkyl- and aryl-N-sulphinylamines. For the alkyl compounds the β effect is seen to produce a decrease in screening and the opposite influence from the γ effect is also observed. An exception to the general tendency for the β effect is noted for (CH3)3CNSO. CNDO/S parameterized nitrogen screening calculations show that for this molecule the distorted cis form, with all of the methyl carbons rotated out of the CNSO plane, is the most probable structure. A similar effect is observed upon substituting the bulky tert-butyl group in the 2 position of the aryl compounds studied. Nitrogen screening calculations again indicate the presence of the distorted cis form. PB - John Wiley & Sons Limited VL - 15 UR - http://dx.doi.org/10.1002/mrc.1270150306 ER - TY - JOUR T1 - Badanie modelu rozgalezionej makroczasteczki metoda Monte Carlo. I. Statystyka konformacyjna (Monte Carlo Study of Star-branched Macromolecules by Means of the Monte Carlo Method. I. Conformational Statistics) JF - Polimery Y1 - 1981 A1 - Andrzej Orszagh A1 - Andrzej Koliński A1 - Andrzej Sikorski VL - 26 ER - TY - JOUR T1 - Badanie modelu rozgalezionej makroczasteczki metoda Monte Carlo. II. Rozmiary klebka statystycznego (Monte Carlo Study of Star-branched Macromolecules by Means of the Monte Carlo Method. II. Analysis of the Coil Dimensions) JF - Polimery Y1 - 1981 A1 - Andrzej Orszagh A1 - Andrzej Koliński A1 - Andrzej Sikorski VL - 26 ER - TY - JOUR T1 - Monte Carlo Study of Concentrated Polymer Solutions JF - Acta Physica Polonica Y1 - 1981 A1 - Andrzej Orszagh A1 - Andrzej Koliński A1 - Jadwiga Duda VL - A59 ER - TY - JOUR T1 - 13C Chemical shifts of some azaindolizines versus electron charge distribution JF - Journal of Molecular Structure Y1 - 1980 A1 - Michal Witanowski A1 - L. Stefaniak A1 - Wanda Sicinska A1 - Graham A. Webb AB - Azaindolizines, which contain all possible combinations of nitrogen atoms within the five-membered ring moiety, are used as models for the investigation of a relationship between electron charge distribution and 13C shifts. A linear correlation is observed between the shifts and total rather than π-charge densities as calculated by the INDO-MO method. The average excitation energy (AEE) approximation in the theory of nuclear screening is shown to hold separately for the CH moieties and the carbon atoms at the ring junction in indolizines. An empirical correlation with charge densities is obtained from the AEE method, as a result of the compensation of effects within the local paramagnetic term and the prevailing contribution to the latter of the effective nuclear charge.13C shifts afford a reasonable measure of the total net charges at the carbon atoms of indolizines. The İNDO calculations indicate that the π-charges follow the pattern suggested by simple resonance structures but the overall charge density depends heavily on σ-core polarization effects.

VL - 64 UR - http://www.sciencedirect.com/science/article/pii/0022286080801116 ER - TY - JOUR T1 - Molar Excess Enthalpies and Volumes of Mixtures of 2,4,6-trimethylopyridyne with some Aliphatic Alcohols JF - Polish Journal of Chemistry Y1 - 1980 A1 - B. Kowalski A1 - Teresa Kasprzycka-Guttman A1 - Andrzej Koliński VL - 54 ER - TY - JOUR T1 - Monte Carlo Method for Statistical Thermodynamics of Polymer Chains JF - Acta Physica Polonica Y1 - 1980 A1 - Andrzej Orszagh A1 - Jadwiga Les A1 - Andrzej Koliński VL - A58 ER - TY - JOUR T1 - Stochastyczna symulacja rodnikowej polimeryzacji w roztworze (Stochastic Simulation of the Free-radical Polymerization in Solution) JF - Polimery Y1 - 1980 A1 - Andrzej Orszagh ED - Andrzej Koliński VL - 25 ER - TY - JOUR T1 - Computer Modeling of Radiation-Induced in-Source Solid-State Polymerizations JF - Polymer Y1 - 1979 A1 - Andrzej Orszagh A1 - Andrzej Koliński A1 - Piotr Romiszowski VL - 20 ER - TY - JOUR T1 - Zastosowanie metody Monte Carlo do badania rozmiarow klebka makromolekularnego w roztworze (Application of the Monte Carlo Method in Studying the Macromolecular Coil Dimensions in Solution) JF - Polimery Y1 - 1978 A1 - Andrzej Orszagh ED - Andrzej Koliński VL - 23 ER - TY - JOUR T1 - Komputerowa symulacja roztworu polimeru metoda Monte Carlo (Computer Simulation of Polymer Solution by Means of the Monte Carlo Method) JF - Polimery Y1 - 1977 A1 - Andrzej Orszagh ED - Andrzej Koliński VL - 22 ER -