%0 Journal Article %J Biochemical Society Transactions %D 2013 %T Knotting pathways in proteins. %A Joanna I. Sulkowska %A Noel, Jeffrey K %A Ramírez-Sarmiento, César A %A Rawdon, Eric J %A Millett, Kenneth C %A Onuchic, José N %K Animals %K Humans %K Protein Conformation %K Protein Engineering %K Protein Folding %K Proteins %K Thermodynamics %X 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. %B Biochemical Society Transactions %V 41 %P 523-7 %8 2013 Apr %G eng %N 2 %R 10.1042/BST20120342 %0 Journal Article %J Proceedings of the National Academy of Sciences of the United States of America %D 2012 %T Conservation of complex knotting and slipknotting patterns in proteins. %A Joanna I. Sulkowska %A Rawdon, Eric J %A Millett, Kenneth C %A Onuchic, José N %A Stasiak, Andrzej %K Protein Conformation %K Protein Folding %K Proteins %X 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. %B Proceedings of the National Academy of Sciences of the United States of America %V 109 %P E1715-23 %8 2012 Jun 26 %G eng %N 26 %R 10.1073/pnas.1205918109 %0 Journal Article %J Proceedings of the National Academy of Sciences of the United States of America %D 2012 %T Energy landscape of knotted protein folding. %A Joanna I. Sulkowska %A Noel, Jeffrey K %A Onuchic, José N %K Evolution, Molecular %K Kinetics %K Models, Molecular %K Molecular Dynamics Simulation %K Mutation %K Protein Folding %K Proteins %X 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. %B Proceedings of the National Academy of Sciences of the United States of America %V 109 %P 17783-8 %8 2012 Oct 30 %G eng %N 44 %R 10.1073/pnas.1201804109 %0 Journal Article %J Journal of c\Computational Chemistry %D 2011 %T CABS-NMR–De novo tool for rapid global fold determination from chemical shifts, residual dipolar couplings and sparse methyl-methyl NOEs %A Dorota Latek %A Andrzej Koliński %K Algorithms %K Animals %K Cattle %K Magnetic Resonance Spectroscopy %K Magnetic Resonance Spectroscopy: methods %K Models %K Molecular %K Monte Carlo Method %K Protein Conformation %K Protein Folding %K Proteins %K Proteins: chemistry %K S100 Proteins %K S100 Proteins: chemistry %X 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. %B Journal of c\Computational Chemistry %V 32 %P 536–44 %G eng %U http://www.ncbi.nlm.nih.gov/pubmed/20806263 %R 10.1002/jcc.21640 %0 Journal Article %J Journal of the American Chemical Society %D 2011 %T Simulation of chaperonin effect on protein folding: a shift from nucleation-condensation to framework mechanism %A Sebastian Kmiecik %A Andrzej Koliński %K Chaperonins %K Chaperonins: metabolism %K Computational Biology %K Models %K Molecular %K Protein Conformation %K protein dynamics %K Protein Folding %K Protein Structure %K Staphylococcal Protein A %K Staphylococcal Protein A: chemistry %K Staphylococcal Protein A: metabolism %K Stochastic Processes %K Tertiary %X

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.

%B Journal of the American Chemical Society %V 133 %P 10283–9 %8 jul %G eng %U http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3132998&tool=pmcentrez&rendertype=abstract %R 10.1021/ja203275f %0 Journal Article %J Proceedings of the National Academy of Sciences of the United States of America %D 2010 %T Slipknotting upon native-like loop formation in a trefoil knot protein. %A Noel, Jeffrey K %A Joanna I. Sulkowska %A Onuchic, José N %K Algorithms %K Archaea %K Archaeal Proteins %K Crystallization %K Databases, Protein %K Models, Molecular %K Molecular Dynamics Simulation %K Protein Conformation %K Protein Folding %K Protein Multimerization %K Protein Structure, Secondary %K Protein Structure, Tertiary %K Thermodynamics %X 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. %B Proceedings of the National Academy of Sciences of the United States of America %V 107 %P 15403-8 %8 2010 Aug 31 %G eng %N 35 %R 10.1073/pnas.1009522107 %0 Journal Article %J PLoS Comput Biol %D 2010 %T A Stevedore's protein knot. %A Bölinger, Daniel %A Joanna I. Sulkowska %A Hsu, Hsiao-Ping %A Mirny, Leonid A %A Kardar, Mehran %A Onuchic, José N %A Virnau, Peter %K Databases, Protein %K Hydrolases %K Molecular Dynamics Simulation %K Protein Conformation %K Protein Folding %X 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. %B PLoS Comput Biol %V 6 %P e1000731 %8 2010 Apr %G eng %N 4 %R 10.1371/journal.pcbi.1000731 %0 Journal Article %J Proceedings of the National Academy of Sciences of the United States of America %D 2009 %T Dodging the crisis of folding proteins with knots. %A Joanna I. Sulkowska %A Sułkowski, Piotr %A Onuchic, José %K Kinetics %K Models, Molecular %K Protein Folding %K Protein Structure, Tertiary %K Proteins %X 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. %B Proceedings of the National Academy of Sciences of the United States of America %V 106 %P 3119-24 %8 2009 Mar 3 %G eng %N 9 %R 10.1073/pnas.0811147106 %0 Journal Article %J Phys Rev Lett %D 2009 %T Jamming proteins with slipknots and their free energy landscape. %A Joanna I. Sulkowska %A Sułkowski, Piotr %A Onuchic, José N %K Protein Conformation %K Protein Folding %K Proteins %K Thermodynamics %K Time Factors %X 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. %B Phys Rev Lett %V 103 %P 268103 %8 2009 Dec 31 %G eng %N 26 %0 Journal Article %J PLoS Comput Biol %D 2009 %T Mechanical strength of 17,134 model proteins and cysteine slipknots. %A Sikora, Mateusz %A Joanna I. Sulkowska %A Cieplak, Marek %K Amino Acids %K Cysteine %K elasticity %K Humans %K Models, Molecular %K Molecular Dynamics Simulation %K Protein Folding %K Proteins %K Tensile Strength %X 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. %B PLoS Comput Biol %V 5 %P e1000547 %8 2009 Oct %G eng %N 10 %R 10.1371/journal.pcbi.1000547 %0 Journal Article %J Proceedings of the National Academy of Sciences of the United States of America %D 2009 %T On the remarkable mechanostability of scaffoldins and the mechanical clamp motif. %A Valbuena, Alejandro %A Oroz, Javier %A Hervás, Rubén %A Vera, Andrés Manuel %A Rodríguez, David %A Menéndez, Margarita %A Joanna I. Sulkowska %A Cieplak, Marek %A Carrión-Vázquez, Mariano %K Amino Acid Motifs %K Biotechnology %K Cellulose %K Clostridium thermocellum %K Computer Simulation %K Databases, Protein %K Kinetics %K Microscopy, Atomic Force %K Nanotechnology %K Protein Conformation %K Protein Engineering %K Protein Folding %K Protein Structure, Secondary %K Proteins %K Stress, Mechanical %X 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. %B Proceedings of the National Academy of Sciences of the United States of America %V 106 %P 13791-6 %8 2009 Aug 18 %G eng %N 33 %R 10.1073/pnas.0813093106 %0 Journal Article %J BMC Structural Biology %D 2008 %T Contact prediction in protein modeling: scoring, folding and refinement of coarse-grained models %A Dorota Latek %A Andrzej Koliński %K Algorithms %K Caspase 6 %K Caspase 6: chemistry %K Caspase 6: genetics %K Computer Simulation %K Databases %K Models %K Molecular %K Protein %K Protein Folding %K Proteins %K Proteins: chemistry %K Proteins: genetics %X

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.

%B BMC Structural Biology %V 8 %P 36 %8 jan %G eng %U http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2527566&tool=pmcentrez&rendertype=abstract %R 10.1186/1472-6807-8-36 %0 Journal Article %J Biophysical Journal %D 2008 %T Folding pathway of the b1 domain of protein G explored by multiscale modeling %A Sebastian Kmiecik %A Andrzej Koliński %K Chemical %K coarse-grained modeling %K Computer Simulation %K Models %K Molecular %K Molecular Dynamics Simulation %K Nerve Tissue Proteins %K Nerve Tissue Proteins: chemistry %K Nerve Tissue Proteins: ultrastructure %K Protein Conformation %K protein dynamics %K Protein Folding %K Protein Structure %K Tertiary %X 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. %B Biophysical Journal %I Elsevier %V 94 %P 726–36 %8 feb %G eng %U http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2186257&tool=pmcentrez&rendertype=abstract %R 10.1529/biophysj.107.116095 %0 Journal Article %J Biophys J %D 2008 %T Selection of optimal variants of Gō-like models of proteins through studies of stretching. %A Joanna I. Sulkowska %A Cieplak, Marek %K Analysis of Variance %K Biomechanical Phenomena %K Models, Molecular %K Protein Conformation %K Protein Folding %K Proteins %K Reproducibility of Results %K Temperature %K Thermodynamics %X 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. %B Biophys J %V 95 %P 3174-91 %8 2008 Oct %G eng %N 7 %R 10.1529/biophysj.107.127233 %0 Journal Article %J Proceedings of the National Academy of Sciences of the United States of America %D 2008 %T Stabilizing effect of knots on proteins. %A Joanna I. Sulkowska %A Sulkowski, Piotr %A Szymczak, P %A Cieplak, Marek %K Computer Simulation %K Disulfides %K Hot Temperature %K Humans %K Models, Chemical %K Ornithine Carbamoyltransferase %K Protein Folding %K Protein Structure, Secondary %K Stress, Mechanical %X 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. %B Proceedings of the National Academy of Sciences of the United States of America %V 105 %P 19714-9 %8 2008 Dec 16 %G eng %N 50 %R 10.1073/pnas.0805468105 %0 Journal Article %J Proceedings of the National Academy of Sciences of the United States of America %D 2007 %T Characterization of protein-folding pathways by reduced-space modeling %A Sebastian Kmiecik %A Andrzej Koliński %K Amino Acid Sequence %K coarse-grained modeling %K Computational Biology %K Computer Simulation %K Hydrophobic and Hydrophilic Interactions %K Models %K Molecular %K Molecular Dynamics Simulation %K Monte Carlo Method %K Protein Denaturation %K protein dynamics %K Protein Folding %K Protein Structure %K Proteins %K Proteins: chemistry %K Proteins: metabolism %K Temperature %K Tertiary %X 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. %B Proceedings of the National Academy of Sciences of the United States of America %V 104 %P 12330–5 %8 jul %G eng %U http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1941469&tool=pmcentrez&rendertype=abstract %R 10.1073/pnas.0702265104 %0 Journal Article %J Journal of Computational Chemistry %D 2007 %T Protein structure prediction: combining de novo modeling with sparse experimental data %A Dorota Latek %A Dariusz Ekonomiuk %A Andrzej Koliński %K Algorithms %K Computer Simulation %K Magnetic Resonance Spectroscopy %K Models %K Molecular %K Protein Folding %K Protein Structure %K Proteins %K Proteins: chemistry %K Secondary %K Software %X 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. %B Journal of Computational Chemistry %V 28 %P 1668–76 %8 jul %G eng %U http://www.ncbi.nlm.nih.gov/pubmed/17342709 %R 10.1002/jcc.20657 %0 Journal Article %J Acta Biochimica Polonica %D 2006 %T Denatured proteins and early folding intermediates simulated in a reduced conformational space %A Sebastian Kmiecik %A Mateusz Kurcinski %A Aleksandra Rutkowska %A Dominik Gront %A Andrzej Koliński %K Animals %K Biophysics %K Biophysics: methods %K Chymotrypsin %K Chymotrypsin: antagonists & inhibitors %K Chymotrypsin: chemistry %K Computer Simulation %K Cytochromes c %K Cytochromes c: chemistry %K Models %K Molecular %K Molecular Conformation %K Monte Carlo Method %K Protein Conformation %K Protein Denaturation %K Protein Folding %K Ribonucleases %K Ribonucleases: chemistry %K src Homology Domains %K Statistical %X 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. %B Acta Biochimica Polonica %V 53 %P 131–143 %8 jan %G eng %U http://www.ncbi.nlm.nih.gov/pubmed/16365636 %0 Journal Article %J International Journal of Quantum Chemistry %D 2005 %T Exploring protein energy landscapes with hierarchical clustering %A Dominik Gront %A Ulrich H. E. Hansmann %A Andrzej Koliński %K energy landscape %K hierarchical clustering %K homology %K modeling %K monte carlo sampling %K Protein Folding %K protein lattice model %X 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. %B International Journal of Quantum Chemistry %V 105 %P 826–830 %G eng %U http://onlinelibrary.wiley.com/doi/10.1002/qua.20741/full %0 Journal Article %J Proteins %D 2005 %T Generalized protein structure prediction based on combination of fold-recognition with de novo folding and evaluation of models %A Andrzej Koliński %A Janusz M. Bujnicki %K Algorithms %K Computational Biology %K Computational Biology: methods %K Computer Simulation %K Computers %K Data Interpretation %K Databases %K Dimerization %K Models %K Molecular %K Monte Carlo Method %K Protein %K Protein Conformation %K Protein Folding %K Protein Structure %K Proteomics %K Proteomics: methods %K Reproducibility of Results %K Secondary %K Sequence Alignment %K Software %K Statistical %K Tertiary %X 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. %B Proteins %V 61 Suppl. 7 %P 84–90 %8 jan %G eng %U http://www.ncbi.nlm.nih.gov/pubmed/16187348 %R 10.1002/prot.20723 %0 Journal Article %J The Journal of Chemical Physics %D 2005 %T A minimal proteinlike lattice model: an alpha-helix motif %A Piotr Pokarowski %A Karol Droste %A Andrzej Koliński %K Algorithms %K Computer Simulation %K Hydrophobic and Hydrophilic Interactions %K Protein Folding %K Protein Structure %K Proteins %K Proteins: chemistry %K Secondary %K Thermodynamics %X A simple protein model of a four-helix bundle motif on a face-centered cubic lattice has been studied. Total energy of a conformation includes attractive interactions between hydrophobic residues, repulsive interactions between hydrophobic and polar residues, and a potential that favors helical turns. Using replica exchange Monte Carlo simulations we have estimated a set of parameters for which the native structure is a global minimum of conformational energy. Then we have shown that all the above types of interactions are necessary to guarantee the cooperativity of folding transition and to satisfy the thermodynamic hypothesis. %B The Journal of Chemical Physics %V 122 %P 214915 %8 jun %G eng %U http://www.ncbi.nlm.nih.gov/pubmed/15974798 %R 10.1063/1.1924601 %0 Journal Article %J Acta Biochimica Polonica %D 2005 %T Protein modeling with reduced representation: statistical potentials and protein folding mechanism %A Dariusz Ekonomiuk %A Marcin Kielbasinski %A Andrzej Koliński %K Biophysical Phenomena %K Biophysics %K Computer Simulation %K Models %K Molecular %K Monte Carlo Method %K Protein Conformation %K Protein Folding %K Proteins %K Proteins: chemistry %K Proteins: metabolism %X 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. %B Acta Biochimica Polonica %V 52 %P 741–8 %8 jan %G eng %U http://www.ncbi.nlm.nih.gov/pubmed/15933762 %0 Journal Article %J Proceedings of the National Academy of Sciences of the United States of America %D 2005 %T Theoretical model of prion propagation: a misfolded protein induces misfolding %A Edyta Małolepsza %A Michal Boniecki %A Andrzej Koliński %A Lucjan Piela %K Amino Acid Sequence %K Amino Acids %K Amino Acids: metabolism %K Computer Simulation %K Models %K Molecular %K Monte Carlo Method %K Prions %K Prions: metabolism %K Protein Conformation %K Protein Folding %K Theoretical %X 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. %B Proceedings of the National Academy of Sciences of the United States of America %V 102 %P 7835–40 %8 may %@ 0409389102 %G eng %U http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1142357&tool=pmcentrez&rendertype=abstract %R 10.1073/pnas.0409389102 %0 Journal Article %J J Chem Phys %D 2005 %T Thermal unfolding of proteins. %A Cieplak, Marek %A Joanna I. Sulkowska %K Chemistry, Physical %K Computer Simulation %K Connectin %K Kinetics %K Models, Molecular %K Molecular Conformation %K Muscle Proteins %K Protein Conformation %K Protein Denaturation %K Protein Folding %K Protein Kinases %K Protein Structure, Secondary %K Proteins %K Temperature %K Time Factors %X 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. %B J Chem Phys %V 123 %P 194908 %8 2005 Nov 15 %G eng %N 19 %R 10.1063/1.2121668 %0 Journal Article %J Polymer %D 2004 %T Reduced models of proteins and their applications %A Andrzej Koliński %A Jeffrey Skolnick %K Lattice proteins %K Protein Folding %K Reduced protein models %X 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. %B Polymer %V 45 %P 511–524 %8 jan %G eng %U http://www.sciencedirect.com/science/article/pii/S0032386103009923 http://linkinghub.elsevier.com/retrieve/pii/S0032386103009923 %R 10.1016/j.polymer.2003.10.064 %0 Journal Article %J Biophysical Journal %D 2003 %T A minimal physically realistic protein-like lattice model: designing an energy landscape that ensures all-or-none folding to a unique native state %A Piotr Pokarowski %A Andrzej Koliński %A Jeffrey Skolnick %K Amino Acid Motifs %K Computer Simulation %K Crystallography %K Crystallography: methods %K Energy Transfer %K Entropy %K Mechanical %K Models %K Molecular %K Monte Carlo Method %K Peptides %K Peptides: chemistry %K Protein Conformation %K Protein Folding %K Protein Structure %K Proteins %K Proteins: chemistry %K Static Electricity %K Stress %K Tertiary %X 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. %B Biophysical Journal %V 84 %P 1518–26 %8 mar %G eng %U http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1302725&tool=pmcentrez&rendertype=abstract %R 10.1016/S0006-3495(03)74964-9 %0 Journal Article %J Biopolymers %D 2003 %T A simple lattice model that exhibits a protein-like cooperative all-or-none folding transition %A Andrzej Koliński %A Dominik Gront %A Piotr Pokarowski %A Jeffrey Skolnick %K Biopolymers %K Biopolymers: chemistry %K Biopolymers: metabolism %K Chemical %K Models %K Molecular %K Monte Carlo Method %K Protein Folding %K Protein Structure %K Proteins %K Proteins: chemistry %K Proteins: metabolism %K Secondary %K Thermodynamics %X 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). %B Biopolymers %V 69 %P 399–405 %8 jul %G eng %U http://www.ncbi.nlm.nih.gov/pubmed/12833266 %R 10.1002/bip.10385 %0 Journal Article %J Biophysical Journal %D 2003 %T TOUCHSTONE II: a new approach to ab initio protein structure prediction %A Yang Zhang %A Andrzej Koliński %A Jeffrey Skolnick %K Algorithms %K Amino Acid Sequence %K Computer Simulation %K Crystallography %K Crystallography: methods %K Energy Transfer %K Models %K Molecular %K Molecular Sequence Data %K Protein %K Protein Conformation %K Protein Folding %K Protein Structure %K Protein: methods %K Proteins %K Proteins: chemistry %K Secondary %K Sequence Analysis %K Software %K Static Electricity %K Statistical %X 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. %B Biophysical Journal %V 85 %P 1145–64 %G eng %U http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1303233&tool=pmcentrez&rendertype=abstract %R 10.1016/S0006-3495(03)74551-2 %0 Journal Article %J Proteins %D 2003 %T TOUCHSTONEX: protein structure prediction with sparse NMR data %A Wei Li %A Yang Zhang %A Daisuke Kihara %A Yuanpeng Janet Huang %A Deyou Zheng %A Gaetano T. Montelione %A Andrzej Koliński %A Jeffrey Skolnick %K Algorithms %K Amino Acids %K Models, Molecular %K Nuclear Magnetic Resonance, Biomolecular %K Protein Conformation %K Protein Folding %K Protein Structure, Tertiary %K Proteins %K Staphylococcal Protein A %X 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. %B Proteins %V 53 %P 290-306 %8 2003 Nov 1 %G eng %N 2 %R 10.1002/prot.10499 %0 Journal Article %J Biophysical Journal %D 2003 %T Unfolding of globular proteins: monte carlo dynamics of a realistic reduced model %A Andrzej Koliński %A Piotr Klein %A Piotr Romiszowski %A Jeffrey Skolnick %K Apoproteins %K Apoproteins: chemistry %K Bacterial Proteins %K Chemical %K DNA-Binding Proteins %K DNA-Binding Proteins: chemistry %K Leghemoglobin %K Leghemoglobin: chemistry %K Models %K Molecular %K Monte Carlo Method %K Myoglobin %K Myoglobin: chemistry %K Nerve Tissue Proteins %K Nerve Tissue Proteins: chemistry %K Plastocyanin %K Plastocyanin: chemistry %K Protein Denaturation %K Protein Folding %K Proteins %K Proteins: chemistry %K Statistical %X 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. %B Biophysical Journal %V 85 %P 3271–3278 %8 nov %G eng %U http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1303603&tool=pmcentrez&rendertype=abstract %R 10.1016/S0006-3495(03)74745-6 %0 Journal Article %J Proceedings of the National Academy of Sciences of the United States of America %D 2002 %T Ab initio protein structure prediction on a genomic scale: application to the Mycoplasma genitalium genome %A Daisuke Kihara %A Yang Zhang %A Hui Lu %A Andrzej Koliński %A Jeffrey Skolnick %K Algorithms %K Bacterial %K Databases as Topic %K Genome %K Models %K Molecular %K Monte Carlo Method %K Mycoplasma %K Mycoplasma: genetics %K Protein Folding %K Proteins %K Proteins: chemistry %K Software %X 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. %B Proceedings of the National Academy of Sciences of the United States of America %V 99 %P 5993–5998 %8 apr %G eng %U http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=122890&tool=pmcentrez&rendertype=abstract %R 10.1073/pnas.092135699 %0 Journal Article %J Acta Biochimica Polonica %D 2002 %T Computer simulations of protein folding with a small number of distance restraints %A Andrzej Sikorski %A Andrzej Koliński %A Jeffrey Skolnick %K Algorithms %K Amino Acids %K Amino Acids: chemistry %K Chemical %K Computer Simulation %K Hydrogen Bonding %K Models %K Molecular %K Monte Carlo Method %K Nerve Tissue Proteins %K Nerve Tissue Proteins: chemistry %K Plastocyanin %K Plastocyanin: chemistry %K Protein Conformation %K Protein Folding %K Protein Kinases %K Thermodynamics %X 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. %B Acta Biochimica Polonica %V 49 %P 683–692 %8 jan %G eng %U http://www.ncbi.nlm.nih.gov/pubmed/12422238 %R 024903683 %0 Journal Article %J Biophysical Journal %D 2002 %T Numerical study of the entropy loss of dimerization and the folding thermodynamics of the GCN4 leucine zipper %A Jorge Viñals %A Andrzej Koliński %A Jeffrey Skolnick %K Biophysical Phenomena %K Biophysics %K Databases as Topic %K Dimerization %K DNA-Binding Proteins %K DNA-Binding Proteins: chemistry %K Entropy %K Hot Temperature %K Leucine Zippers %K Models %K Monte Carlo Method %K Protein Folding %K Protein Kinases %K Protein Kinases: chemistry %K Saccharomyces cerevisiae Proteins %K Saccharomyces cerevisiae Proteins: chemistry %K Temperature %K Theoretical %K Thermodynamics %X 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. %B Biophysical Journal %V 83 %P 2801–2811 %8 nov %G eng %U http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1302364&tool=pmcentrez&rendertype=abstract %R 10.1016/S0006-3495(02)75289-2 %0 Journal Article %J Current Pharmaceutical Biotechnology %D 2002 %T The protein folding problem: a biophysical enigma %A Jacquelyn S. Fetrow %A A. Giammona %A Andrzej Koliński %A Jeffrey Skolnick %K Animals %K Biophysical Phenomena %K Biophysics %K Computational Biology %K Computational Biology: methods %K Computational Biology: trends %K Humans %K Protein Folding %X 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. %B Current Pharmaceutical Biotechnology %V 3 %P 329–347 %8 dec %G eng %U http://www.ncbi.nlm.nih.gov/pubmed/12463416 %0 Journal Article %J Proteins %D 2001 %T Ab initio protein structure prediction via a combination of threading, lattice folding, clustering, and structure refinement %A Jeffrey Skolnick %A Andrzej Koliński %A Daisuke Kihara %A Marcos Betancourt %A Piotr Rotkiewicz %A Michal Boniecki %K carlo methods %K casp4 %K lattice models %K monte %K Protein Folding %K protein struc- %K structure %K threading %K ture prediction %X 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. %B Proteins %V 45 %P 149–156 %G eng %U http://onlinelibrary.wiley.com/doi/10.1002/prot.1172/full %N Suppl. S5 CASP4 %R 10.1002/prot.1172 %0 Journal Article %J Proteins %D 2001 %T Generalized comparative modeling (GENECOMP): a combination of sequence comparison, threading, and lattice modeling for protein structure prediction and refinement %A Andrzej Koliński %A Marcos Betancourt %A Daisuke Kihara %A Piotr Rotkiewicz %A Jeffrey Skolnick %K Algorithms %K Chemical %K Combinatorial Chemistry Techniques %K Combinatorial Chemistry Techniques: methods %K Computational Biology %K Computational Biology: methods %K Computer Simulation %K Databases %K Factual %K Models %K Molecular %K Monte Carlo Method %K Protein Folding %K Proteins %K Proteins: chemistry %K Sequence Alignment %K Sequence Alignment: methods %X 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. %B Proteins %V 44 %P 133–149 %8 aug %G eng %U http://www.ncbi.nlm.nih.gov/pubmed/11391776 %0 Journal Article %J Polish Journal of Chemistry %D 2001 %T Structure of proteins: New approach to molecular modeling %A Andrzej Koliński %A Piotr Rotkiewicz %A Jeffrey Skolnick %K comperative modeling %K lattice protein models %K loop modeling %K Monte Carlo simulations %K Protein Folding %K protein structure prediction %B Polish Journal of Chemistry %V 75 %P 587–599 %G eng %U http://baztech.icm.edu.pl/baztech/cgi-bin/btgetdoc.cgi?BUJ1-0017-0036 %0 Journal Article %J Proceedings of the National Academy of Sciences of the United States of America %D 2001 %T TOUCHSTONE: an ab initio protein structure prediction method that uses threading-based tertiary restraints %A Daisuke Kihara %A Hui Lu %A Andrzej Koliński %A Jeffrey Skolnick %K Algorithms %K Computer Simulation %K Models %K Molecular %K Monte Carlo Method %K Protein Folding %K Protein Structure %K Proteins %K Proteins: chemistry %K Tertiary %X 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. %B Proceedings of the National Academy of Sciences of the United States of America %V 98 %P 10125–30 %8 aug %G eng %U http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=56926&tool=pmcentrez&rendertype=abstract %R 10.1073/pnas.181328398 %0 Journal Article %J Proteins %D 2000 %T Computer simulations of the properties of the alpha2, alpha2C, and alpha2D de novo designed helical proteins %A Andrzej Sikorski %A Andrzej Koliński %A Jeffrey Skolnick %K Amino Acid Sequence %K Computer Simulation %K Drug Design %K Molecular Sequence Data %K Protein Folding %K Protein Structure %K Proteins %K Proteins: chemistry %K Secondary %K Thermodynamics %X 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. %B Proteins %V 38 %P 17–28 %8 jan %G eng %U http://www.ncbi.nlm.nih.gov/pubmed/10651035 %0 Journal Article %J Acta Poloniae Pharmaceutica – Drug Research %D 2000 %T Monte Carlo simulation of designed helical proteins %A Andrzej Sikorski %A Andrzej Koliński %A Jeffrey Skolnick %K Monte Carlo Method %K Protein Conformation %K Protein Folding %K Protein Structure, Secondary %B Acta Poloniae Pharmaceutica – Drug Research %V 57 Suppl %P 119-21 %8 2000 Nov %G eng %0 Journal Article %J Nature Biotechnology %D 2000 %T Structural genomics and its importance for gene function analysis %A Jeffrey Skolnick %A Jacquelyn S. Fetrow %A Andrzej Koliński %K Animals %K Computer Simulation %K Databases %K Evolution %K Factual %K Genome %K Humans %K Internet %K Molecular %K Molecular Biology %K Molecular Biology: methods %K Protein Folding %K Structure-Activity Relationship %X 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. %B Nature Biotechnology %V 18 %P 283–287 %8 mar %G eng %U http://www.ncbi.nlm.nih.gov/pubmed/10700142 %R 10.1038/73723 %0 Journal Article %J Proteins %D 1999 %T Ab initio folding of proteins using restraints derived from evolutionary information %A Angel. R. Ortiz %A Andrzej Koliński %A Piotr Rotkiewicz %A Bartosz Ilkowski %A Jeffrey Skolnick %K Algorithms %K Amino Acid Sequence %K Evolution %K Models %K Molecular %K Molecular Sequence Data %K Monte Carlo Method %K Protein Folding %K Proteins %K Proteins: chemistry %X 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. %B Proteins %V Suppl. 3 %P 177–185 %8 jan %G eng %U http://www.ncbi.nlm.nih.gov/pubmed/10526366 %0 Journal Article %J Biophysical Journal %D 1999 %T De novo simulations of the folding thermodynamics of the GCN4 leucine zipper %A Debasisa Mohanty %A Andrzej Koliński %A Jeffrey Skolnick %K Computer Simulation %K Dimerization %K DNA-Binding Proteins %K Fungal Proteins %K Fungal Proteins: chemistry %K Leucine Zippers %K Monte Carlo Method %K Protein Conformation %K Protein Denaturation %K Protein Folding %K Protein Kinases %K Protein Kinases: chemistry %K Protein Structure %K Saccharomyces cerevisiae Proteins %K Secondary %K Temperature %K Thermodynamics %X 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. %B Biophysical Journal %V 77 %P 54–69 %8 jul %@ 6197848821 %G eng %U http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1300312&tool=pmcentrez&rendertype=abstract %R 10.1016/S0006-3495(99)76872-4 %0 Journal Article %J Biophysical Journal %D 1999 %T Dynamics and thermodynamics of beta-hairpin assembly: insights from various simulation techniques %A Andrzej Koliński %A Bartosz Ilkowski %A Jeffrey Skolnick %K Amino Acid Sequence %K Animals %K Biophysical Phenomena %K Biophysics %K Models %K Molecular %K Molecular Sequence Data %K Monte Carlo Method %K Nerve Tissue Proteins %K Nerve Tissue Proteins: chemistry %K Protein Conformation %K Protein Folding %K Protein Structure %K Proteins %K Proteins: chemistry %K Secondary %K Thermodynamics %X 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. %B Biophysical Journal %V 77 %P 2942–52 %8 dec %G eng %U http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1300567&tool=pmcentrez&rendertype=abstract %R 10.1016/S0006-3495(99)77127-4 %0 Journal Article %J Proteins %D 1998 %T Assembly of protein structure from sparse experimental data: an efficient Monte Carlo model %A Andrzej Koliński %A Jeffrey Skolnick %K Algorithms %K Computer Simulation %K Models %K Molecular %K Monte Carlo Method %K Protein Conformation %K Protein Folding %K Protein Structure %K Secondary %K Tertiary %X 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. %B Proteins %V 32 %P 475–494 %8 sep %G eng %U http://www.ncbi.nlm.nih.gov/pubmed/9726417 %0 Journal Article %J Biophysical Journal %D 1998 %T Computer simulations of de novo designed helical proteins %A Andrzej Sikorski %A Andrzej Koliński %A Jeffrey Skolnick %K Amino Acid Sequence %K Biophysical Phenomena %K Biophysics %K Computer Simulation %K Dimerization %K Drug Design %K Hydrogen Bonding %K Models %K Molecular %K Molecular Sequence Data %K Monte Carlo Method %K Protein Conformation %K Protein Folding %K Protein Structure %K Proteins %K Proteins: chemistry %K Secondary %K Thermodynamics %X 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. %B Biophysical Journal %V 75 %P 92–105 %8 jul %G eng %U http://www.ncbi.nlm.nih.gov/pubmed/10651035 %R 10.1016/S0006-3495(98)77497-1 %0 Journal Article %J Journal of Molecular Biology %D 1998 %T Fold assembly of small proteins using monte carlo simulations driven by restraints derived from multiple sequence alignments %A Angel. R. Ortiz %A Andrzej Koliński %A Jeffrey Skolnick %K Amino Acid Sequence %K Chemical %K Models %K Molecular Sequence Data %K Monte Carlo Method %K Protein Folding %K Protein Structure %K Secondary %K Tertiary %X 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. %B Journal of Molecular Biology %V 277 %P 419–448 %8 mar %G eng %U http://www.ncbi.nlm.nih.gov/pubmed/9514747 %R 10.1006/jmbi.1997.1595 %0 Journal Article %J Proceedings of the National Academy of Sciences of the United States of America %D 1998 %T Nativelike topology assembly of small proteins using predicted restraints in Monte Carlo folding simulations %A Angel. R. Ortiz %A Andrzej Koliński %A Jeffrey Skolnick %K Algorithms %K Models %K Molecular %K Monte Carlo Method %K Protein Folding %K Protein Structure %K Secondary %K Sequence Alignment %K Software %K Tertiary %X 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. %B Proceedings of the National Academy of Sciences of the United States of America %V 95 %P 1020–1025 %8 feb %G eng %U http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=18658&tool=pmcentrez&rendertype=abstract %0 Journal Article %J Proteins %D 1998 %T Tertiary structure prediction of the KIX domain of CBP using Monte Carlo simulations driven by restraints derived from multiple sequence alignments %A Angel. R. Ortiz %A Andrzej Koliński %A Jeffrey Skolnick %K Algorithms %K Amino Acid Sequence %K CREB-Binding Protein %K Databases as Topic %K Models %K Molecular %K Molecular Sequence Data %K Monte Carlo Method %K Mutation %K Mutation: genetics %K Nuclear Proteins %K Nuclear Proteins: chemistry %K Protein Folding %K Protein Structure %K Secondary %K Sequence Alignment %K Tertiary %K Trans-Activators %K Transcription Factors %K Transcription Factors: chemistry %X 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). %B Proteins %V 30 %P 287–294 %G eng %U http://www.ncbi.nlm.nih.gov/pubmed/9517544 %0 Journal Article %J Proteins %D 1997 %T A method for the prediction of surface "U"-turns and transglobular connections in small proteins %A Andrzej Koliński %A Jeffrey Skolnick %A Adam Godzik %A Wei-Ping Hu %K Algorithms %K Amino Acid Sequence %K Animals %K Humans %K Molecular Sequence Data %K Protein Folding %K Protein Structure %K Proteins %K Proteins: chemistry %K Secondary %X 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%. %B Proteins %V 27 %P 290–308 %8 feb %G eng %U http://www.ncbi.nlm.nih.gov/pubmed/9061792 %0 Journal Article %J Journal of Molecular Biology %D 1997 %T MONSSTER: a method for folding globular proteins with a small number of distance restraints %A Jeffrey Skolnick %A Andrzej Koliński %A Angel. R. Ortiz %K Algorithms %K Aprotinin %K Aprotinin: chemistry %K Bacterial Proteins %K Bacterial Proteins: chemistry %K Computer Graphics %K Computer Simulation %K Flavodoxin %K Flavodoxin: chemistry %K Models %K Molecular %K Myoglobin %K Myoglobin: chemistry %K Plastocyanin %K Plastocyanin: chemistry %K Protein Conformation %K Protein Folding %K Protein Structure %K Secondary %K Tertiary %K Thioredoxins %K Thioredoxins: chemistry %X 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. %B Journal of Molecular Biology %V 265 %P 217–241 %8 jan %G eng %U http://www.ncbi.nlm.nih.gov/pubmed/9020984 %R 10.1006/jmbi.1996.0720 %0 Journal Article %J Protein Engineering %D 1996 %T Does a backwardly read protein sequence have a unique native state? %A Krzysztof A. Olszewski %A Andrzej Koliński %A Jeffrey Skolnick %K Amino Acid Sequence %K Computer Simulation %K Models %K Molecular %K Molecular Sequence Data %K Monte Carlo Method %K Protein Conformation %K Protein Engineering %K Protein Folding %K Protein Structure %K Secondary %K Staphylococcal Protein A %K Staphylococcal Protein A: chemistry %K Tertiary %X 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. %B Protein Engineering %V 9 %P 5–14 %8 jan %G eng %U http://www.ncbi.nlm.nih.gov/pubmed/9053902 %0 Journal Article %J Proteins %D 1996 %T Folding simulations and computer redesign of protein A three-helix bundle motifs %A Krzysztof A. Olszewski %A Andrzej Koliński %A Jeffrey Skolnick %K Computer Simulation %K Monte Carlo Method %K Mutation %K Protein Conformation %K Protein Folding %K Staphylococcal Protein A %K Staphylococcal Protein A: chemistry %X 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. %B Proteins %V 25 %P 286–299 %8 jul %G eng %U http://www.ncbi.nlm.nih.gov/pubmed/8844865 %R 10.1002/(SICI)1097-0134(199607)25:3<286::AID-PROT2>3.0.CO;2-E %0 Journal Article %J Biochemistry %D 1996 %T Method for predicting the state of association of discretized protein models. Application to leucine zippers. %A Michal Vieth %A Andrzej Koliński %A Jeffrey Skolnick %K Amino Acid Sequence %K Leucine Zippers %K Molecular Sequence Data %K Protein Folding %X 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. %B Biochemistry %V 35 %P 955–967 %G eng %U http://www.ncbi.nlm.nih.gov/pubmed/8547278 %R 10.1021/bi9520702 %0 Journal Article %J Proteins %D 1996 %T On the origin of the cooperativity of protein folding: implications from model simulations %A Andrzej Koliński %A Wojciech Galazka %A Jeffrey Skolnick %K Amino Acids %K Amino Acids: chemistry %K Chemical %K Computer Simulation %K Models %K Molecular %K Protein Conformation %K Protein Folding %K Thermodynamics %X 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. %B Proteins %V 26 %P 271–287 %8 nov %@ 1028610297 %G eng %U http://www.ncbi.nlm.nih.gov/pubmed/8953649 %R 10.1002/(SICI)1097-0134(199611)26:3<271::AID-PROT4>3.0.CO;2-H %0 Journal Article %J Protein Science: a Publication of the Protein Society %D 1995 %T Are proteins ideal mixtures of amino acids? Analysis of energy parameter sets %A Adam Godzik %A Andrzej Koliński %A Jeffrey Skolnick %K Amino Acid Sequence %K Amino Acids %K Crystallography %K Databases %K Factual %K Magnetic Resonance Spectroscopy %K Mathematics %K Models %K Protein Conformation %K Protein Folding %K Proteins %K Proteins: chemistry %K Theoretical %K Thermodynamics %K X-Ray %X 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. %B Protein Science: a Publication of the Protein Society %V 4 %P 2107–2117 %8 oct %G eng %U http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2142984&tool=pmcentrez&rendertype=abstract %R 10.1002/pro.5560041016 %0 Journal Article %J Journal of Molecular Biology %D 1995 %T Prediction of quaternary structure of coiled coils. Application to mutants of the GCN4 leucine zipper %A Michal Vieth %A Andrzej Koliński %A Charles L. Brooks III %A Jeffrey Skolnick %K Computer Simulation %K DNA-Binding Proteins %K Fungal Proteins %K Fungal Proteins: chemistry %K Hydrogen Bonding %K Leucine Zippers %K Monte Carlo Method %K Mutation %K Protein Conformation %K Protein Folding %K Protein Kinases %K Protein Kinases: chemistry %K Saccharomyces cerevisiae Proteins %K Thermodynamics %X 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. %B Journal of Molecular Biology %V 251 %P 448–67 %8 aug %G eng %U http://www.ncbi.nlm.nih.gov/pubmed/7650742 %R 10.1006/jmbi.1995.0447 %0 Journal Article %J Proteins %D 1994 %T Monte Carlo simulations of protein folding. I. Lattice model and interaction scheme %A Andrzej Koliński %A Jeffrey Skolnick %K Amino Acid Sequence %K Amino Acids %K Computer Simulation %K Hydrogen Bonding %K Models, Chemical %K Models, Molecular %K Models, Theoretical %K Molecular Sequence Data %K Monte Carlo Method %K Protein Folding %K Protein Structure, Tertiary %X 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. %B Proteins %V 18 %P 338-52 %8 1994 Apr %G eng %N 4 %R 10.1002/prot.340180405 %0 Journal Article %J Proceedings of the National Academy of Sciences of the United States of America %D 1993 %T From independent modules to molten globules: observations on the nature of protein folding intermediates %A Jeffrey Skolnick %A Andrzej Koliński %A Adam Godzik %K Binding Sites %K Isomerases %K Isomerases: chemistry %K Protein Disulfide-Isomerases %K Protein Folding %K Protein Structure %K Proteins %K Proteins: chemistry %K Secondary %B Proceedings of the National Academy of Sciences of the United States of America %V 90 %P 2099–100 %G eng %U http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=46030&tool=pmcentrez&rendertype=abstract %0 Journal Article %J Journal of Molecular Biology %D 1991 %T Dynamic Monte Carlo Simulations of a new lattice model of globular protein folding, structure, and dynamics %A Jeffrey Skolnick %A Andrzej Koliński %K assembly mechanism %K bends and turns %K folding pathways %K Protein Folding %K secondary structures %X 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. %B Journal of Molecular Biology %V 221 %P 499–531 %G eng %U http://dx.doi.org/10.1016/0022-2836(91)80070-B %R 10.1016/0022-2836(91)80070-B