%0 Journal Article %J Biophysical Journal %D 2012 %T Coarse-grained modeling of mucus barrier properties %A Pawel Gniewek %A Andrzej Koliński %K Adhesives %K Adhesives: chemistry %K Adhesives: metabolism %K Glycocalyx %K Glycocalyx: chemistry %K Glycocalyx: metabolism %K Models %K Molecular %K Mucins %K Mucins: chemistry %K Mucins: metabolism %K Mucus %K Mucus: chemistry %K Mucus: cytology %K Mucus: metabolism %K Nanoparticles %K Nanoparticles: chemistry %K Protein Conformation %K Surface Properties %X

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

%B Biophysical Journal %V 102 %P 195–200 %8 jan %G eng %U http://www.ncbi.nlm.nih.gov/pubmed/22339855 %R 10.1016/j.bpj.2011.11.4010 %0 Journal Article %J International Journal of Molecular Medicine %D 2011 %T Analysis and optimization of interactions between peptides mimicking the GD2 ganglioside and the monoclonal antibody 14G2a %A Irena Horwacik %A Mateusz Kurcinski %A Malgorzata Bzowska %A Aleksandra K. Kowalczyk %A Dominik Czaplicki %A Andrzej Koliński %A Hanna Rokita %K Amino Acid Sequence %K Antibodies %K Binding Sites %K Cell Line %K Gangliosides %K Gangliosides: immunology %K Humans %K Models %K Molecular %K Molecular Mimicry %K Molecular Sequence Data %K Monoclonal %K Monoclonal: chemistry %K Monoclonal: immunology %K Neuroblastoma %K Neuroblastoma: genetics %K Neuroblastoma: immunology %K Peptide Library %K Peptides %K Peptides: chemistry %K Peptides: immunology %K Structure-Activity Relationship %K Tumor %X

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

%B International Journal of Molecular Medicine %V 28 %P 47–57 %8 jul %G eng %U http://www.ncbi.nlm.nih.gov/pubmed/21455557 %R 10.3892/ijmm.2011.655 %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 Acta Biochimica Polonica %D 2011 %T Computational study of binding of epothilone A to β-tubulin %A Karol Kamel %A Andrzej Koliński %K Animals %K Binding Sites %K Cattle %K Computer Simulation %K Epothilones %K Epothilones: chemistry %K Hydrogen Bonding %K Models %K Molecular %K Protein Binding %K Thermodynamics %K Tubulin %K Tubulin: chemistry %X Understanding the interactions of epothilones with β-tubulin is crucial for computer aided rational design of macrocyclic drugs based on epothilones and epothilone derivatives. Despite numerous structure-activity relationship investigations we still lack substantial knowledge about the binding mode of epothilones and their derivatives to β-tubulin. In this work, we reevaluated the electron crystallography structure of epothilone A/β-tubulin complex (PDB entry 1TVK) and proposed an alternative binding mode of epothilone A to β-tubulin that explains more experimental facts. %B Acta Biochimica Polonica %V 58 %P 255–60 %8 jan %G eng %U http://www.ncbi.nlm.nih.gov/pubmed/21633729 %0 Conference Proceedings %B Proceedings of the National Academy of Sciences of the United States of America %D 2011 %T Human telomerase model shows the role of the TEN domain in advancing the double helix for the next polymerization step %A Kamil Steczkiewicz %A Michael T. Zimmermann %A Mateusz Kurcinski %A Benjamin A. Lewis %A Drena Dobbs %A Andrzej Kloczkowski %A Robert L. Jernigan %A Andrzej Koliński %A Krzysztof Ginalski %K Amino Acid %K Amino Acid Sequence %K Binding Sites %K Binding Sites: genetics %K Catalytic Domain %K Computer Simulation %K DNA %K DNA: chemistry %K DNA: genetics %K DNA: metabolism %K Humans %K Kinetics %K Models %K Molecular %K Molecular Sequence Data %K Nucleic Acid Conformation %K Nucleic Acid Heteroduplexes %K Nucleic Acid Heteroduplexes: chemistry %K Nucleic Acid Heteroduplexes: genetics %K Nucleic Acid Heteroduplexes: metabolism %K Polymerization %K Protein Binding %K Protein Structure %K RNA %K RNA: chemistry %K RNA: genetics %K RNA: metabolism %K Secondary %K Sequence Homology %K Telomerase %K Telomerase: chemistry %K Telomerase: genetics %K Telomerase: metabolism %K Telomere %K Telomere: chemistry %K Telomere: genetics %K Telomere: metabolism %K Tertiary %X Telomerases constitute a group of specialized ribonucleoprotein enzymes that remediate chromosomal shrinkage resulting from the "end-replication" problem. Defects in telomere length regulation are associated with several diseases as well as with aging and cancer. Despite significant progress in understanding the roles of telomerase, the complete structure of the human telomerase enzyme bound to telomeric DNA remains elusive, with the detailed molecular mechanism of telomere elongation still unknown. By application of computational methods for distant homology detection, comparative modeling, and molecular docking, guided by available experimental data, we have generated a three-dimensional structural model of a partial telomerase elongation complex composed of three essential protein domains bound to a single-stranded telomeric DNA sequence in the form of a heteroduplex with the template region of the human RNA subunit, TER. This model provides a structural mechanism for the processivity of telomerase and offers new insights into elongation. We conclude that the RNADNA heteroduplex is constrained by the telomerase TEN domain through repeated extension cycles and that the TEN domain controls the process by moving the template ahead one base at a time by translation and rotation of the double helix. The RNA region directly following the template can bind complementarily to the newly synthesized telomeric DNA, while the template itself is reused in the telomerase active site during the next reaction cycle. This first structural model of the human telomerase enzyme provides many details of the molecular mechanism of telomerase and immediately provides an important target for rational drug design. %B Proceedings of the National Academy of Sciences of the United States of America %V 108 %P 9443–8 %8 jun %G eng %U http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3111281&tool=pmcentrez&rendertype=abstract %R 10.1073/pnas.1015399108 %0 Journal Article %J Proteins %D 2011 %T Multibody coarse-grained potentials for native structure recognition and quality assessment of protein models %A Pawel Gniewek %A Sumudu P. Leelananda %A Andrzej Koliński %A Robert L. Jernigan %A Andrzej Kloczkowski %K Amino Acids %K Amino Acids: chemistry %K Computational Biology %K Computational Biology: methods %K Models %K Molecular %K Protein Conformation %K Proteins %K Proteins: chemistry %X Multibody potentials have been of much interest recently because they take into account three dimensional interactions related to residue packing and capture the cooperativity of these interactions in protein structures. Our goal was to combine long range multibody potentials and short range potentials to improve recognition of native structure among misfolded decoys. We optimized the weights for four-body nonsequential, four-body sequential, and short range potentials to obtain optimal model ranking results for threading and have compared these data against results obtained with other potentials (26 different coarse-grained potentials from the Potentials 'R'Us web server have been used). Our optimized multibody potentials outperform all other contact potentials in the recognition of the native structure among decoys, both for models from homology template-based modeling and from template-free modeling in CASP8 decoy sets. We have compared the results obtained for this optimized coarse-grained potentials, where each residue is represented by a single point, with results obtained by using the DFIRE potential, which takes into account atomic level information of proteins. We found that for all proteins larger than 80 amino acids our optimized coarse-grained potentials yield results comparable to those obtained with the atomic DFIRE potential. %B Proteins %V 79 %P 1923–9 %8 jun %G eng %U http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3093657&tool=pmcentrez&rendertype=abstract %R 10.1002/prot.23015 %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 BMC Structural Biology %D 2010 %T Modeling of loops in proteins: a multi-method approach %A Michal Jamroz %A Andrzej Koliński %K Databases %K Models %K Molecular %K Protein %K Protein Structure %K Proteins %K Proteins: chemistry %K Software %K Tertiary %X BACKGROUND: Template-target sequence alignment and loop modeling are key components of protein comparative modeling. Short loops can be predicted with high accuracy using structural fragments from other, not necessairly homologous proteins, or by various minimization methods. For longer loops multiscale approaches employing coarse-grained de novo modeling techniques should be more effective. RESULTS: For a representative set of protein structures of various structural classes test predictions of loop regions have been performed using MODELLER, ROSETTA, and a CABS coarse-grained de novo modeling tool. Loops of various length, from 4 to 25 residues, were modeled assuming an ideal target-template alignment of the remaining portions of the protein. It has been shown that classical modeling with MODELLER is usually better for short loops, while coarse-grained de novo modeling is more effective for longer loops. Even very long missing fragments in protein structures could be effectively modeled. Resolution of such models is usually on the level 2-6 A, which could be sufficient for guiding protein engineering. Further improvement of modeling accuracy could be achieved by the combination of different methods. In particular, we used 10 top ranked models from sets of 500 models generated by MODELLER as multiple templates for CABS modeling. On average, the resulting molecular models were better than the models from individual methods. CONCLUSIONS: Accuracy of protein modeling, as demonstrated for the problem of loop modeling, could be improved by the combinations of different modeling techniques. %B BMC Structural Biology %V 10 %P 5 %8 jan %G eng %U http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2837870&tool=pmcentrez&rendertype=abstract %R 10.1186/1472-6807-10-5 %0 Journal Article %J The Journal of Steroid Biochemistry and Molecular Biology %D 2010 %T Theoretical study of molecular mechanism of binding TRAP220 coactivator to Retinoid X Receptor alpha, activated by 9-cis retinoic acid %A Mateusz Kurcinski %A Andrzej Koliński %K Binding Sites %K Cell Nucleus %K Cell Nucleus: metabolism %K Computer Simulation %K Crystallography %K Humans %K Ligands %K Mediator Complex Subunit 1 %K Mediator Complex Subunit 1: metabolism %K Models %K Molecular %K Molecular Conformation %K Peptides %K Peptides: chemistry %K Protein Binding %K Protein Structure %K Retinoid X Receptor alpha %K Retinoid X Receptor alpha: metabolism %K Tertiary %K Theoretical %K Tretinoin %K Tretinoin: metabolism %K X-Ray %K X-Ray: methods %X

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

%B The Journal of Steroid Biochemistry and Molecular Biology %I Elsevier Ltd %V 121 %P 124–9 %8 jul %G eng %U http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2906686&tool=pmcentrez&rendertype=abstract %R 10.1016/j.jsbmb.2010.03.086 %0 Journal Article %J Acta Biochimica Polonica %D 2010 %T TRACER. A new approach to comparative modeling that combines threading with free-space conformational sampling %A Sebastian Trojanowski %A Aleksandra Rutkowska %A Andrzej Koliński %K Computational Biology %K Computational Biology: methods %K Imaging %K Models %K Molecular %K Protein Conformation %K Proteins %K Proteins: chemistry %K Three-Dimensional %K Three-Dimensional: methods %X A new approach to comparative modeling of proteins, TRACER, is described and benchmarked against classical modeling procedures. The new method unifies true three-dimensional threading with coarse-grained sampling of query protein conformational space. The initial sequence alignment of a query protein with a template is not required, although a template needs to be somehow identified. The template is used as a multi-featured fuzzy three-dimensional scaffold. The conformational search for the query protein is guided by intrinsic force field of the coarse-grained modeling engine CABS and by compatibility with the template scaffold. During Replica Exchange Monte Carlo simulations the model chain representing the query protein finds the best possible structural alignment with the template chain, that also optimizes the intra-protein interactions as approximated by the knowledge based force field of CABS. The benchmark done for a representative set of query/template pairs of various degrees of sequence similarity showed that the new method allows meaningful comparative modeling also for the region of marginal, or non-existing, sequence similarity. Thus, the new approach significantly extends the applicability of comparative modeling. %B Acta Biochimica Polonica %V 57 %P 125–33 %8 jan %G eng %U http://www.ncbi.nlm.nih.gov/pubmed/20309433 %0 Journal Article %J Journal of Structural and Functional Genomics %D 2009 %T Distance matrix-based approach to protein structure prediction %A Andrzej Kloczkowski %A Robert L. Jernigan %A Zhijun Wu %A Guang Song %A Lei Yang %A Andrzej Koliński %A Piotr Pokarowski %K Binding Sites %K Computer Simulation %K Databases %K Models %K Molecular %K Principal Component Analysis %K Protein %K Protein Conformation %K Proteins %K Proteins: chemistry %X

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

%B Journal of Structural and Functional Genomics %V 10 %P 67–81 %8 mar %G eng %U http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3018873&tool=pmcentrez&rendertype=abstract %R 10.1007/s10969-009-9062-2 %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 Journal of Computer-Aided Molecular Design %D 2008 %T Fast and accurate methods for predicting short-range constraints in protein models %A Dominik Gront %A Andrzej Koliński %K Algorithms %K Amino Acid Sequence %K Models %K Molecular %K Molecular Sequence Data %K Predictive Value of Tests %K Protein %K Proteins %K Proteins: chemistry %K Proteins: genetics %K Proteins: metabolism %K Sequence Analysis %K Software %X

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

%B Journal of Computer-Aided Molecular Design %V 22 %P 783–8 %G eng %U http://www.ncbi.nlm.nih.gov/pubmed/18415023 %R 10.1007/s10822-008-9213-8 %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 Biophysical journal %D 2008 %T Predicting the complex structure and functional motions of the outer membrane transporter and signal transducer FecA %A Taner Z. Sen %A Margaret Kloster %A Robert L. Jernigan %A Andrzej Koliński %A Janusz M. Bujnicki %A Andrzej Kloczkowski %K Cell Membrane %K Cell Membrane: chemistry %K Cell Surface %K Cell Surface: chemistry %K Cell Surface: ultrastructure %K Chemical %K Computer Simulation %K Escherichia coli Proteins %K Escherichia coli Proteins: chemistry %K Escherichia coli Proteins: ultrastructure %K Models %K Molecular %K Motion %K Protein Conformation %K Receptors %X Escherichia coli requires an efficient transport and signaling system to successfully sequester iron from its environment. FecA, a TonB-dependent protein, serves a critical role in this process: first, it binds and transports iron in the form of ferric citrate, and second, it initiates a signaling cascade that results in the transcription of several iron transporter genes in interaction with inner membrane proteins. The structure of the plug and barrel domains and the periplasmic N-terminal domain (NTD) are separately available. However, the linker connecting the plug and barrel and the NTD domains is highly mobile, which may prevent the determination of the FecA structure as a whole assembly. Here, we reduce the conformation space of this linker into most probable structural models using the modeling tool CABS, then apply normal-mode analysis to investigate the motions of the whole structure of FecA by using elastic network models. We relate the FecA domain motions to the outer-inner membrane communication, which initiates transcription. We observe that the global motions of FecA assign flexibility to the TonB box and the NTD, and control the exposure of the TonB box for binding to the TonB inner membrane protein, suggesting how these motions relate to FecA function. Our simulations suggest the presence of a communication between the loops on both ends of the protein, a signaling mechanism by which a signal could be transmitted by conformational transitions in response to the binding of ferric citrate. %B Biophysical journal %I Elsevier %V 94 %P 2482–91 %8 apr %@ 5152944294 %G eng %U http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2267147&tool=pmcentrez&rendertype=abstract %R 10.1529/biophysj.107.116046 %0 Journal Article %J Cell Cycle (Georgetown, Tex.) %D 2008 %T Uncharacterized DUF1574 leptospira proteins are SGNH hydrolases %A Lukasz Knizewski %A Kamil Steczkiewicz %A Krzysztof Kuchta %A Lucjan Wyrwicz %A Dariusz Plewczynski %A Andrzej Koliński %A Leszek Rychlewski %A Krzysztof Ginalski %K Amino Acid Sequence %K Bacterial Proteins %K Bacterial Proteins: genetics %K Base Sequence %K Computational Biology %K DNA %K Hydrolases %K Hydrolases: genetics %K Leptospira %K Leptospira: enzymology %K Models %K Molecular %K Molecular Sequence Data %K Sequence Alignment %K Sequence Analysis %B Cell Cycle (Georgetown, Tex.) %V 7 %P 542–4 %8 feb %G eng %U http://www.ncbi.nlm.nih.gov/pubmed/18235229 %0 Journal Article %J Journal of Computational Chemistry %D 2007 %T Backbone building from quadrilaterals: a fast and accurate algorithm for protein backbone reconstruction from alpha carbon coordinates %A Dominik Gront %A Sebastian Kmiecik %A Andrzej Koliński %K Algorithms %K Carbon %K Carbon: chemistry %K Models %K Molecular %K Proteins %K Proteins: chemistry %X In this contribution, we present an algorithm for protein backbone reconstruction that comprises very high computational efficiency with high accuracy. Reconstruction of the main chain atomic coordinates from the alpha carbon trace is a common task in protein modeling, including de novo structure prediction, comparative modeling, and processing experimental data. The method employed in this work follows the main idea of some earlier approaches to the problem. The details and careful design of the present approach are new and lead to the algorithm that outperforms all commonly used earlier applications. BBQ (Backbone Building from Quadrilaterals) program has been extensively tested both on native structures as well as on near-native decoy models and compared with the different available existing methods. Obtained results provide a comprehensive benchmark of existing tools and evaluate their applicability to a large scale modeling using a reduced representation of protein conformational space. The BBQ package is available for downloading from our website at http://www.bioshell.pl/BBQ This webpage also provides a user manual that describes BBQ functions in detail. %B Journal of Computational Chemistry %V 28 %P 1593–7 %8 jul %G eng %U http://onlinelibrary.wiley.com/doi/10.1002/jcc.20624/full http://www.ncbi.nlm.nih.gov/pubmed/17342707 %R 10.1002/jcc.20624 %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 Bioinformatics (Oxford, England) %D 2007 %T Comparative modeling without implicit sequence alignments %A Andrzej Koliński %A Dominik Gront %K Algorithms %K Amino Acid Sequence %K Chemical %K Computer Simulation %K Models %K Molecular %K Molecular Sequence Data %K Protein %K Protein Conformation %K Protein: methods %K Proteins %K Proteins: chemistry %K Proteins: ultrastructure %K Sequence Alignment %K Sequence Alignment: methods %K Sequence Analysis %X

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

%B Bioinformatics (Oxford, England) %V 23 %P 2522–7 %G eng %U http://www.ncbi.nlm.nih.gov/pubmed/17660201 %R 10.1093/bioinformatics/btm380 %0 Journal Article %J Journal of Molecular Modeling %D 2007 %T Hierarchical modeling of protein interactions %A Mateusz Kurcinski %A Andrzej Koliński %K Algorithms %K Amino Acid Sequence %K Amino Acids %K Amino Acids: analysis %K Carbon %K Carbon: chemistry %K Computer Simulation %K Crystallography %K Hydrogen Bonding %K Models %K Molecular %K Monte Carlo Method %K Peptides %K Peptides: chemistry %K Peptides: metabolism %K Protein Binding %K Protein Conformation %K Protein Structure %K Proteins %K Proteins: chemistry %K Proteins: metabolism %K Secondary %K Stereoisomerism %K Theoretical %K X-Ray %X A novel approach to hierarchical peptide-protein and protein-protein docking is described and evaluated. Modeling procedure starts from a reduced space representation of proteins and peptides. Polypeptide chains are represented by strings of alpha-carbon beads restricted to a fine-mesh cubic lattice. Side chains are represented by up to two centers of interactions, corresponding to beta-carbons and the centers of mass of the remaining portions of the side groups, respectively. Additional pseudoatoms are located in the centers of the virtual bonds connecting consecutive alpha carbons. These pseudoatoms support a model of main-chain hydrogen bonds. Docking starts from a collection of random configurations of modeled molecules. Interacting molecules are flexible; however, higher accuracy models are obtained when the conformational freedom of one (the larger one) of the assembling molecules is limited by a set of weak distance restraints extracted from the experimental (or theoretically predicted) structures. Sampling is done by means of Replica Exchange Monte Carlo method. Afterwards, the set of obtained structures is subject to a hierarchical clustering. Then, the centroids of the resulting clusters are used as scaffolds for the reconstruction of the atomic details. Finally, the all-atom models are energy minimized and scored using classical tools of molecular mechanics. The method is tested on a set of macromolecular assemblies consisting of proteins and peptides. It is demonstrated that the proposed approach to the flexible docking could be successfully applied to prediction of protein-peptide and protein-protein interactions. The obtained models are almost always qualitatively correct, although usually of relatively low (or moderate) resolution. In spite of this limitation, the proposed method opens new possibilities of computational studies of macromolecular recognition and mechanisms of assembly of macromolecular complexes. %B Journal of Molecular Modeling %V 13 %P 691–698 %8 jul %G eng %U http://www.ncbi.nlm.nih.gov/pubmed/17297609 %R 10.1007/s00894-007-0177-8 %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 The Journal of Steroid Biochemistry and Molecular Biology %D 2007 %T Steps towards flexible docking: modeling of three-dimensional structures of the nuclear receptors bound with peptide ligands mimicking co-activators' sequences %A Mateusz Kurcinski %A Andrzej Koliński %K Amino Acid Sequence %K Crystallography %K Cytoplasmic and Nuclear %K Cytoplasmic and Nuclear: chemistry %K Cytoplasmic and Nuclear: metabolism %K Ligands %K Models %K Molecular %K Molecular Mimicry %K Peptides %K Peptides: chemistry %K Peptides: metabolism %K Protein Binding %K Protein Structure %K Quaternary %K Receptors %K X-Ray %X We developed a fully flexible docking method that uses a reduced lattice representation of protein molecules, adapted for modeling peptide-protein complexes. The CABS model (Carbon Alpha, Carbon Beta, Side Group) employed here, incorporates three pseudo-atoms per residue-Calpha, Cbeta and the center of the side group instead of full-atomic protein representation. Force field used by CABS was derived from statistical analysis of non-redundant database of protein structures. Application of our method included modeling of the complexes between various nuclear receptors (NRs) and peptide co-activators, for which three-dimensional structures are known. We tried to rebuild the native state of the complexes, starting from separated components. Accuracy of the best obtained models, calculated as coordinate root-mean-square deviation (cRMSD) between the target and the modeled structures, was under 1A, which is competitive with experimental methods, such as crystallography or NMR. Forthcoming modeling study should lead to better understanding of mechanisms of macromolecular assembly and will explain co-activators' effects on receptors activity, especially on vitamin D receptor and other nuclear receptors. %B The Journal of Steroid Biochemistry and Molecular Biology %V 103 %P 357–60 %8 mar %G eng %U http://www.ncbi.nlm.nih.gov/pubmed/17241780 %R 10.1016/j.jsbmb.2006.12.059 %0 Journal Article %J BMC Structural Biology %D 2007 %T Towards the high-resolution protein structure prediction. Fast refinement of reduced models with all-atom force field %A Sebastian Kmiecik %A Dominik Gront %A Andrzej Koliński %K Computer Simulation %K Models %K Molecular %K Protein Structure %K protein structure prediction %K Proteins %K Proteins: chemistry %K Secondary %K Software %K Tertiary %K Time Factors %X BACKGROUND: Although experimental methods for determining protein structure are providing high resolution structures, they cannot keep the pace at which amino acid sequences are resolved on the scale of entire genomes. For a considerable fraction of proteins whose structures will not be determined experimentally, computational methods can provide valuable information. The value of structural models in biological research depends critically on their quality. Development of high-accuracy computational methods that reliably generate near-experimental quality structural models is an important, unsolved problem in the protein structure modeling. RESULTS: Large sets of structural decoys have been generated using reduced conformational space protein modeling tool CABS. Subsequently, the reduced models were subject to all-atom reconstruction. Then, the resulting detailed models were energy-minimized using state-of-the-art all-atom force field, assuming fixed positions of the alpha carbons. It has been shown that a very short minimization leads to the proper ranking of the quality of the models (distance from the native structure), when the all-atom energy is used as the ranking criterion. Additionally, we performed test on medium and low accuracy decoys built via classical methods of comparative modeling. The test placed our model evaluation procedure among the state-of-the-art protein model assessment methods. CONCLUSION: These test computations show that a large scale high resolution protein structure prediction is possible, not only for small but also for large protein domains, and that it should be based on a hierarchical approach to the modeling protocol. We employed Molecular Mechanics with fixed alpha carbons to rank-order the all-atom models built on the scaffolds of the reduced models. Our tests show that a physic-based approach, usually considered computationally too demanding for large-scale applications, can be effectively used in such studies. %B BMC Structural Biology %V 7 %P 43 %8 jan %@ 1472680774 %G eng %U http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1933428&tool=pmcentrez&rendertype=abstract %R 10.1186/1472-6807-7-43 %0 Journal Article %J Bioinformatics (Oxford, England) %D 2007 %T T-Pile–a package for thermodynamic calculations for biomolecules %A Dominik Gront %A Andrzej Koliński %K Algorithms %K Biophysics %K Biophysics: methods %K Computational Biology %K Computational Biology: methods %K Computers %K Hot Temperature %K Models %K Molecular Conformation %K Monte Carlo Method %K Probability %K Proteins %K Proteins: chemistry %K Software %K Temperature %K Theoretical %K Thermodynamics %X Molecular dynamics and Monte Carlo, usually conducted in canonical ensemble, deliver a plethora of biomolecular conformations. Proper analysis of the simulation data is a crucial part of biophysical and bioinformatics studies. Sequence alignment problem can be also formulated in terms of Boltzmann distribution. Therefore tools for efficient analysis of canonical ensemble data become extremely valuable. T-Pile package, presented here provides a user-friendly implementation of most important algorithms such as multihistogram analysis and reweighting technique. The package can be used in studies of virtually any system governed by Boltzmann distribution. AVAILABILITY: T-Pile can be downloaded from: http://biocomp.chem.uw.edu.pl/services/tpile. These pages provide a comprehensive tutorial and documentation with illustrative examples of applications. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. %B Bioinformatics (Oxford, England) %V 23 %P 1840–1842 %8 jul %G eng %U http://www.ncbi.nlm.nih.gov/pubmed/17510173 %R 10.1093/bioinformatics/btm259 %0 Journal Article %J BMC Structural Biology %D 2007 %T Type II restriction endonuclease R.Eco29kI is a member of the GIY-YIG nuclease superfamily %A Elena M. Ibryashkina %A Marina V. Zakharova %A Vladimir B. Baskunov %A Ekaterina S. Bogdanova %A Maxim O. Nagornykh %A Marat M Den'mukhamedov %A Bogdan S. Melnik %A Andrzej Koliński %A Dominik Gront %A Marcin Feder %A Alexander S. Solonin %A Janusz M. Bujnicki %K Amino Acid Sequence %K Binding Sites %K Computational Biology %K Computational Biology: methods %K Deoxyribonucleases %K DNA %K DNA Cleavage %K DNA: metabolism %K Electrophoretic Mobility Shift Assay %K Models %K Molecular %K Molecular Sequence Data %K Mutation %K Protein %K Protein Conformation %K Sequence Alignment %K Structural Homology %K Type II Site-Specific %K Type II Site-Specific: chemist %K Type II Site-Specific: metabol %X BACKGROUND: The majority of experimentally determined crystal structures of Type II restriction endonucleases (REases) exhibit a common PD-(D/E)XK fold. Crystal structures have been also determined for single representatives of two other folds: PLD (R.BfiI) and half-pipe (R.PabI), and bioinformatics analyses supported by mutagenesis suggested that some REases belong to the HNH fold. Our previous bioinformatic analysis suggested that REase R.Eco29kI shares sequence similarities with one more unrelated nuclease superfamily, GIY-YIG, however so far no experimental data were available to support this prediction. The determination of a crystal structure of the GIY-YIG domain of homing endonuclease I-TevI provided a template for modeling of R.Eco29kI and prompted us to validate the model experimentally. RESULTS: Using protein fold-recognition methods we generated a new alignment between R.Eco29kI and I-TevI, which suggested a reassignment of one of the putative catalytic residues. A theoretical model of R.Eco29kI was constructed to illustrate its predicted three-dimensional fold and organization of the active site, comprising amino acid residues Y49, Y76, R104, H108, E142, and N154. A series of mutants was constructed to generate amino acid substitutions of selected residues (Y49A, R104A, H108F, E142A and N154L) and the mutant proteins were examined for their ability to bind the DNA containing the Eco29kI site 5'-CCGCGG-3' and to catalyze the cleavage reaction. Experimental data reveal that residues Y49, R104, E142, H108, and N154 are important for the nuclease activity of R.Eco29kI, while H108 and N154 are also important for specific DNA binding by this enzyme. CONCLUSION: Substitutions of residues Y49, R104, H108, E142 and N154 predicted by the model to be a part of the active site lead to mutant proteins with strong defects in the REase activity. These results are in very good agreement with the structural model presented in this work and with our prediction that R.Eco29kI belongs to the GIY-YIG superfamily of nucleases. Our study provides the first experimental evidence for a Type IIP REase that does not belong to the PD-(D/E)XK or HNH superfamilies of nucleases, and is instead a member of the unrelated GIY-YIG superfamily. %B BMC Structural Biology %V 7 %P 48 %8 jan %@ 1472680774 %G eng %U http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1952068&tool=pmcentrez&rendertype=abstract %R 10.1186/1472-6807-7-48 %0 Journal Article %J Biomacromolecules %D 2007 %T Why do proteins divide into domains? Insights from lattice model simulations %A Aleksandra Rutkowska %A Andrzej Koliński %K Computer Simulation %K Models %K Molecular %K Polymers %K Polymers: chemistry %K Protein Structure %K Proteins %K Proteins: chemistry %K Temperature %K Tertiary %X

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

%B Biomacromolecules %V 8 %P 3519–24 %8 nov %G eng %U http://www.ncbi.nlm.nih.gov/pubmed/17929971 %R 10.1021/bm7007718 %0 Journal Article %J Bioinformatics (Oxford, England) %D 2006 %T BioShell–a package of tools for structural biology computations %A Dominik Gront %A Andrzej Koliński %K Chemical %K Computational Biology %K Computational Biology: methods %K Computer Simulation %K Databases %K Models %K Protein %K Protein: methods %K Proteins %K Proteins: analysis %K Proteins: chemistry %K Proteins: classification %K Sequence Alignment %K Sequence Alignment: methods %K Sequence Analysis %K Software %X

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

%B Bioinformatics (Oxford, England) %V 22 %P 621–622 %8 mar %G eng %U http://www.ncbi.nlm.nih.gov/pubmed/16407320 %R 10.1093/bioinformatics/btk037 %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 Journal of Computer-Aided Molecular Design %D 2006 %T Three dimensional model of severe acute respiratory syndrome coronavirus helicase ATPase catalytic domain and molecular design of severe acute respiratory syndrome coronavirus helicase inhibitors %A Marcin Hoffmann %A Krystian Eitner %A Marcin von Grotthuss %A Leszek Rychlewski %A Ewa Banachowicz %A Tomasz Grabarkiewicz %A Tomasz Szkoda %A Andrzej Koliński %K Amino Acid Sequence %K Catalytic Domain %K Conserved Sequence %K DNA Helicases %K DNA Helicases: antagonists & inhibitors %K DNA Helicases: chemistry %K Drug Design %K Enzyme Inhibitors %K Enzyme Inhibitors: pharmacology %K Models %K Molecular %K Molecular Sequence Data %K Protein %K SARS Virus %K SARS Virus: enzymology %K Sequence Alignment %K Structural Homology %K Thermodynamics %X The modeling of the severe acute respiratory syndrome coronavirus helicase ATPase catalytic domain was performed using the protein structure prediction Meta Server and the 3D Jury method for model selection, which resulted in the identification of 1JPR, 1UAA and 1W36 PDB structures as suitable templates for creating a full atom 3D model. This model was further utilized to design small molecules that are expected to block an ATPase catalytic pocket thus inhibit the enzymatic activity. Binding sites for various functional groups were identified in a series of molecular dynamics calculation. Their positions in the catalytic pocket were used as constraints in the Cambridge structural database search for molecules having the pharmacophores that interacted most strongly with the enzyme in a desired position. The subsequent MD simulations followed by calculations of binding energies of the designed molecules were compared to ATP identifying the most successful candidates, for likely inhibitors - molecules possessing two phosphonic acid moieties at distal ends of the molecule. %B Journal of Computer-Aided Molecular Design %V 20 %P 305–319 %8 may %G eng %U http://www.ncbi.nlm.nih.gov/pubmed/16972168 %R 10.1007/s10822-006-9057-z %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 Bioinformatics %D 2005 %T HCPM–program for hierarchical clustering of protein models %A Dominik Gront %A Andrzej Koliński %K Algorithms %K Chemical %K Cluster Analysis %K Computer Simulation %K Internet %K Models %K Molecular %K Protein %K Protein: methods %K Proteins %K Proteins: analysis %K Proteins: chemistry %K Sequence Alignment %K Sequence Alignment: methods %K Sequence Analysis %K Software %K User-Computer Interface %X HCPM is a tool for clustering protein structures from comparative modeling, ab initio structure prediction, etc. A hierarchical clustering algorithm is designed and tested, and a heuristic is provided for an optimal cluster selection. The method has been successfully tested during the CASP6 experiment. %B Bioinformatics %V 21 %P 3179–80 %G eng %U http://www.ncbi.nlm.nih.gov/pubmed/15840705 %R 10.1093/bioinformatics/bti450 %0 Journal Article %J Proteins %D 2005 %T Inferring ideal amino acid interaction forms from statistical protein contact potentials %A Piotr Pokarowski %A Andrzej Kloczkowski %A Robert L. Jernigan %A Neha S. Kothari %A Maria Pokarowska %A Andrzej Koliński %K Amino Acids %K Amino Acids: chemistry %K Binding Sites %K Models %K Molecular %K Proteins %K Proteins: chemistry %K Statistical %K Theoretical %X We have analyzed 29 different published matrices of protein pairwise contact potentials (CPs) between amino acids derived from different sets of proteins, either crystallographic structures taken from the Protein Data Bank (PDB) or computer-generated decoys. Each of the CPs is similar to 1 of the 2 matrices derived in the work of Miyazawa and Jernigan (Proteins 1999;34:49-68). The CP matrices of the first class can be approximated with a correlation of order 0.9 by the formula e(ij) = h(i) + h(j), 1 MOTIVATION: Knowledge-based potentials are valuable tools for protein structure modeling and evaluation of the quality of the structure prediction obtained by a variety of methods. Potentials of such type could be significantly enhanced by a proper exploitation of the evolutionary information encoded in related protein sequences. The new potentials could be valuable components of threading algorithms, ab-initio protein structure prediction, comparative modeling and structure modeling based on fragmentary experimental data. RESULTS: A new potential for scoring local protein geometry is designed and evaluated. The approach is based on the similarity of short protein fragments measured by an alignment of their sequence profiles. Sequence specificity of the resulting energy function has been compared with the specificity of simpler potentials using gapless threading and the ability to predict specific geometry of protein fragments. Significant improvement in threading sensitivity and in the ability to generate sequence-specific protein-like conformations has been achieved.

%B Bioinformatics (Oxford, England) %V 21 %P 981–987 %G eng %U http://www.ncbi.nlm.nih.gov/pubmed/15509604 %R 10.1093/bioinformatics/bti080 %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 Acta Biochimica Polonica %D 2004 %T Protein modeling and structure prediction with a reduced representation %A Andrzej Koliński %K Amino Acid Sequence %K Animals %K Carbon %K Carbon: chemistry %K Crystallography %K Databases as Topic %K Humans %K Hydrogen Bonding %K Mathematics %K Models %K Molecular %K Molecular Sequence Data %K Protein Conformation %K Protein Structure %K Proteins %K Proteins: chemistry %K Proteomics %K Proteomics: methods %K Tertiary %K Theoretical %K X-Ray %X

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

%B Acta Biochimica Polonica %V 51 %P 349–71 %8 jan %G eng %U http://www.ncbi.nlm.nih.gov/pubmed/15218533 %R 035001349 %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 Journal of Computer-Aided Molecular Design %D 2003 %T Protein fragment reconstruction using various modeling techniques %A Michal Boniecki %A Piotr Rotkiewicz %A Jeffrey Skolnick %A Andrzej Koliński %K Amino Acid Sequence %K Binding Sites %K Hydrogen Bonding %K Models %K Molecular %K Peptide Fragments %K Peptide Fragments: chemistry %K Protein Conformation %K Protein Structure %K Proteins %K Proteins: chemistry %K Secondary %X Recently developed reduced models of proteins with knowledge-based force fields have been applied to a specific case of comparative modeling. From twenty high resolution protein structures of various structural classes, significant fragments of their chains have been removed and treated as unknown. The remaining portions of the structures were treated as fixed - i.e., as templates with an exact alignment. Then, the missed fragments were reconstructed using several modeling tools. These included three reduced types of protein models: the lattice SICHO (Side Chain Only) model, the lattice CABS (Calpha + Cbeta + Side group) model and an off-lattice model similar to the CABS model and called REFINER. The obtained reduced models were compared with more standard comparative modeling tools such as MODELLER and the SWISS-MODEL server. The reduced model results are qualitatively better for the higher resolution lattice models, clearly suggesting that these are now mature, competitive and complementary (in the range of sparse alignments) to the classical tools of comparative modeling. Comparison between the various reduced models strongly suggests that the essential ingredient for the sucessful and accurate modeling of protein structures is not the representation of conformational space (lattice, off-lattice, all-atom) but, rather, the specificity of the force fields used and, perhaps, the sampling techniques employed. These conclusions are encouraging for the future application of the fast reduced models in comparative modeling on a genomic scale. %B Journal of Computer-Aided Molecular Design %V 17 %P 725–38 %8 nov %G eng %U http://www.ncbi.nlm.nih.gov/pubmed/15072433 %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 Proteins %D 2003 %T TOUCHSTONE: a unified approach to protein structure prediction. %A Jeffrey Skolnick %A Zhang, Yang %A Arakaki, Adrian K %A Andrzej Koliński %A Michal Boniecki %A Szilágyi, András %A Daisuke Kihara %K Algorithms %K Models %K Molecular %K Protein Conformation %K Protein Structure %K Proteins %K Proteins: chemistry %K Secondary %K Tertiary %X We have applied the TOUCHSTONE structure prediction algorithm that spans the range from homology modeling to ab initio folding to all protein targets in CASP5. Using our threading algorithm PROSPECTOR that does not utilize input from metaservers, one threads against a representative set of PDB templates. If a template is significantly hit, Generalized Comparative Modeling designed to span the range from closely to distantly related proteins from the template is done. This involves freezing the aligned regions and relaxing the remaining structure to accommodate insertions or deletions with respect to the template. For all targets, consensus predicted side chain contacts from at least weakly threading templates are pooled and incorporated into ab initio folding. Often, TOUCHSTONE performs well in the CM to FR categories, with PROSPECTOR showing significant ability to identify analogous templates. When ab initio folding is done, frequently the best models are closer to the native state than the initial template. Among the particularly good predictions are T0130 in the CM/FR category, T0138 in the FR(H) category, T0135 in the FR(A) category, T0170 in the FR/NF category and T0181 in the NF category. Improvements in the approach are needed in the FR/NF and NF categories. Nevertheless, TOUCHSTONE was one of the best performing algorithms over all categories in CASP5. %B Proteins %V CASP Suppl %P 469–79 %8 jan %G eng %U http://www.ncbi.nlm.nih.gov/pubmed/14579335 %R 10.1002/prot.10551 %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 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 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 Proteins %D 2001 %T Model of three-dimensional structure of vitamin D receptor and its binding mechanism with 1alpha,25-dihydroxyvitamin D(3) %A Piotr Rotkiewicz %A Wanda Sicinska %A Andrzej Koliński %A Hector F. DeLuca %K Amino Acid %K Amino Acid Sequence %K Animals %K Binding Sites %K Calcitriol %K Calcitriol: chemistry %K Calcitriol: genetics %K Computational Biology %K Humans %K Ligands %K Models %K Molecular %K Molecular Sequence Data %K Point Mutation %K Protein Conformation %K Protein Structure %K Rats %K Receptors %K Sequence Homology %K Tertiary %X Comparative modeling of the vitamin D receptor three-dimensional structure and computational docking of 1alpha,25-dihydroxyvitamin D(3) into the putative binding pocket of the two deletion mutant receptors: (207-423) and (120-422, Delta [164-207]) are reported and evaluated in the context of extensive mutagenic analysis and crystal structure of holo hVDR deletion protein published recently. The obtained molecular model agrees well with the experimentally determined structure. Six different conformers of 1alpha,25-dihydroxyvitamin D(3) were used to study flexible docking to the receptor. On the basis of values of conformational energy of various complexes and their consistency with functional activity, it appears that 1alpha,25-dihydroxyvitamin D(3) binds the receptor in its 6-s-trans form. The two lowest energy complexes obtained from docking the hormone into the deletion protein (207-423) differ in conformation of ring A and orientation of the ligand molecule in the VDR pocket. 1alpha,25-Dihydroxyvitamin D(3) possessing the A-ring conformation with axially oriented 1alpha-hydroxy group binds receptor with its 25-hydroxy substituent oriented toward the center of the receptor cavity, whereas ligand possessing equatorial conformation of 1alpha-hydroxy enters the pocket with A ring directed inward. The latter conformation and orientation of the ligand is consistent with the crystal structure of hVDR deletion mutant (118-425, Delta [165-215]). The lattice model of rVDR (120-422, Delta [164-207]) shows excellent agreement with the crystal structure of the hVDR mutant. The complex obtained from docking the hormone into the receptor has lower energy than complexes for which homology modeling was used. Thus, a simple model of vitamin D receptor with the first two helices deleted can be potentially useful for designing a general structure of ligand, whereas the advanced lattice model is suitable for examining binding sites in the pocket. %B Proteins %V 44 %P 188–199 %8 2001 %G eng %U http://www.ncbi.nlm.nih.gov/pubmed/11455592 %0 Journal Article %J Protein Engineering %D 2001 %T Three-dimensional modeling of the I-TevI homing endonuclease catalytic domain, a GIY-YIG superfamily member, using NMR restraints and Monte Carlo dynamics %A Janusz M. Bujnicki %A Piotr Rotkiewicz %A Andrzej Koliński %A Leszek Rychlewski %K Algorithms %K Binding Sites %K Biomolecular %K Endodeoxyribonucleases %K Endodeoxyribonucleases: chemistry %K Models %K Molecular %K Monte Carlo Method %K Nuclear Magnetic Resonance %K Protein Structure %K Sequence Alignment %K Tertiary %X Using a recent version of the SICHO algorithm for in silico protein folding, we made a blind prediction of the tertiary structure of the N-terminal, independently folded, catalytic domain (CD) of the I-TevI homing endonuclease, a representative of the GIY-YIG superfamily of homing endonucleases. The secondary structure of the I-TevI CD has been determined using NMR spectroscopy, but computational sequence analysis failed to detect any protein of known tertiary structure related to the GIY-YIG nucleases (Kowalski et al., Nucleic Acids Res., 1999, 27, 2115-2125). To provide further insight into the structure-function relationships of all GIY-YIG superfamily members, including the recently described subfamily of type II restriction enzymes (Bujnicki et al., Trends Biochem. Sci., 2000, 26, 9-11), we incorporated the experimentally determined and predicted secondary and tertiary restraints in a reduced (side chain only) protein model, which was minimized by Monte Carlo dynamics and simulated annealing. The subsequently elaborated full atomic model of the I-TevI CD allows the available experimental data to be put into a structural context and suggests that the GIY-YIG domain may dimerize in order to bring together the conserved residues of the active site. %B Protein Engineering %V 14 %P 717–721 %8 oct %G eng %U http://www.ncbi.nlm.nih.gov/pubmed/11739889 %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 Accurate reconstruction of all-atom protein representations from side-chain-based low-resolution models %A M. Feig %A Piotr Rotkiewicz %A Andrzej Koliński %A Jeffrey Skolnick %A Charles L. Brooks III %K Models %K Molecular %K Proteins %K Proteins: chemistry %X A procedure for the reconstruction of all-atom protein structures from side-chain center-based low-resolution models is introduced and applied to a set of test proteins with high-resolution X-ray structures. The accuracy of the rebuilt all-atom models is measured by root mean square deviations to the corresponding X-ray structures and percentages of correct chi(1) and chi(2) side-chain dihedrals. The benefit of including C(alpha) positions in the low-resolution model is examined, and the effect of lattice-based models on the reconstruction accuracy is discussed. Programs and scripts implementing the reconstruction procedure are made available through the NIH research resource for Multiscale Modeling Tools in Structural Biology (http://mmtsb.scripps.edu). %B Proteins %V 41 %P 86–97 %8 oct %G eng %U http://www.ncbi.nlm.nih.gov/pubmed/10944396 %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 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 1999 %T A method for the improvement of threading-based protein models %A Andrzej Koliński %A Piotr Rotkiewicz %A Bartosz Ilkowski %A Jeffrey Skolnick %K Amino Acid Sequence %K Computer Simulation %K Evaluation Studies as Topic %K Methods %K Models %K Molecular %K Molecular Sequence Data %K Protein Conformation %K Protein Structure %K Proteins %K Proteins: chemistry %K Secondary %K Sequence Alignment %K Software Design %X A new method for the homology-based modeling of protein three-dimensional structures is proposed and evaluated. The alignment of a query sequence to a structural template produced by threading algorithms usually produces low-resolution molecular models. The proposed method attempts to improve these models. In the first stage, a high-coordination lattice approximation of the query protein fold is built by suitable tracking of the incomplete alignment of the structural template and connection of the alignment gaps. These initial lattice folds are very similar to the structures resulting from standard molecular modeling protocols. Then, a Monte Carlo simulated annealing procedure is used to refine the initial structure. The process is controlled by the model's internal force field and a set of loosely defined restraints that keep the lattice chain in the vicinity of the template conformation. The internal force field consists of several knowledge-based statistical potentials that are enhanced by a proper analysis of multiple sequence alignments. The template restraints are implemented such that the model chain can slide along the template structure or even ignore a substantial fraction of the initial alignment. The resulting lattice models are, in most cases, closer (sometimes much closer) to the target structure than the initial threading-based models. All atom models could easily be built from the lattice chains. The method is illustrated on 12 examples of target/template pairs whose initial threading alignments are of varying quality. Possible applications of the proposed method for use in protein function annotation are briefly discussed. %B Proteins %V 37 %P 592–610 %8 dec %G eng %U http://www.ncbi.nlm.nih.gov/pubmed/10651275 %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 Improved method for prediction of protein backbone U-turn positions and major secondary structural elements between U-turns %A Wei-Ping Hu %A Andrzej Koliński %A Jeffrey Skolnick %K Amino Acid %K Amino Acid Sequence %K Amino Acids %K Amino Acids: chemistry %K Data Interpretation %K Models %K Molecular %K Molecular Sequence Data %K Protein Structure %K Proteins %K Proteins: chemistry %K Reproducibility of Results %K Secondary %K Sequence Alignment %K Sequence Alignment: methods %K Sequence Alignment: statistics & numerical data %K Sequence Homology %K Statistical %X A new and more accurate method has been developed for predicting the backbone U-turn positions (where the chain reverses global direction) and the dominant secondary structure elements between U-turns in globular proteins. The current approach uses sequence-specific secondary structure propensities and multiple sequence information. The latter plays an important role in the enhanced success of this approach. Application to two sets (total 108) of small to medium-sized, single-domain proteins indicates that approximately 94% of the U-turn locations are correctly predicted within three residues, as are 88% of dominant secondary structure elements. These results are significantly better than our previous method (Kolinski et al., Proteins 27:290-308, 1997). The current study strongly suggests that the U-turn locations are primarily determined by local interactions. Furthermore, both global length constraints and local interactions contribute significantly to the determination of the secondary structure types between U-turns. Accurate U-turn predictions are crucial for accurate secondary structure predictions in the current method. Protein structure modeling, tertiary structure predictions, and possibly, fold recognition should benefit from the predicted structural data provided by this new method. %B Proteins %V 29 %P 443–460 %G eng %U http://www.ncbi.nlm.nih.gov/pubmed/9408942 %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 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 Biopolymers %D 1989 %T Monte Carlo studies on equilibrium globular protein folding. II. Beta-barrel globular protein models %A Jeffrey Skolnick %A Andrzej Koliński %A Robert Yaris %K Algorithms %K Models %K Monte Carlo Method %K Protein Conformation %K Proteins %K Theoretical %X In the context of dynamic Monte Carlo simulations on a model protein confined to a tetrahedral lattice, the interplay of protein size and tertiary structure, and the requirements for an all-or-none transition to a unique native state, are investigated. Small model proteins having a primary sequence consisting of a central bend neutral region flanked by two tails having an alternating hydrophobic/hydrophilic pattern of residues are seen to undergo a continuous transition to a beta-hairpin collapsed state. On increasing the length of the tails, the beta-hairpin structural motif is found to be in equilibrium with a four-member beta-barrel. Further increase of the tail length results in the shift of the structural equilibrium to the four-member beta-barrel. The random coil to beta-barrel transition is of an all-or-none character, but while the central turn is always the desired native bend, the location of the turns involving the two external strands is variable. That is, beta-barrels having the external stands that are two residues out of register are also observed in the transition region. Introduction into the primary sequence of two additional regions that are at the very least neutral toward turn formation produces an all-or-none transition to the unique, native, four-member beta-barrel. Various factors that can augment the stability of the native conformation are explored. Overall, these folding simulations strongly indicate that the general rules of globular protein folding are rather robust–namely, one requires a general pattern of hydrophobic/hydrophilic residues that allow the protein to have a well-defined interior and exterior and the presence of regions in the amino acid sequence that at the very least are locally indifferent to turn formation. Since no site-specific interactions between hydrophobic and hydrophilic residues are required to produce a unique four-member beta-barrel, these simulations strongly suggest that site specificity is involved in structural fine-tuning. %B Biopolymers %V 28 %P 1059–95 %8 jun %G eng %U http://www.ncbi.nlm.nih.gov/pubmed/2730942 %R 10.1002/bip.360280604 %0 Journal Article %J Biopolymers %D 1987 %T Monte Carlo studies on equilibrium globular protein folding. I. Homopolymeric lattice models of beta-barrel proteins %A Andrzej Koliński %A Jeffrey Skolnick %A Robert Yaris %K Biological %K Models %K Monte Carlo Method %K Protein Conformation %K Proteins %X Dynamic Monte Carlo studies have been performed on various diamond lattice models of β-proteins. Unlike previous work, no bias toward the native state is introduced; instead, the protein is allowed to freely hunt through all of phase space to find the equilibrium conformation. Thus, these systems may aid in the elucidation of the rules governing protein folding from a given primary sequence; in particular, the interplay of short- vs long-range interaction can be explored. Three distinct models (A[BOND]C) were examined. In model A, in addition to the preference for trans (t) over gauche states (g+ and g−) (thereby perhaps favoring β-sheet formation), attractive interactions are allowed between all nonbonded, nearest neighbor pairs of segments. If the molecules possess a relatively large fraction of t states in the denatured form, on cooling spontaneous collapse to a well-defined β-barrel is observed. Unfortunately, in model A the denatured state exhibits too much secondary structure to correctly model the globular protein collapse transition. Thus in models B and C, the local stiffness is reduced. In model B, in the absence of long-range interactions, t and g states are equally weighted, and cooperativity is introduced by favoring formation of adjacent pairs of nonbonded (but not necessarily parallel) t states. While the denatured state of these systems behaves like a random coil, their native globular structure is poorly defined. Model C retains the cooperativity of model B but allows for a slight preference of t over g states in the short-range interactions. Here, the denatured state is indistinguishable from a random coil, and the globular state is a well-defined β-barrel. Over a range of chain lengths, the collapse is well represented by an all-or-none model. Hence, model C possesses the essential qualitative features observed in real globular proteins. These studies strongly suggest that the uniqueness of the globular conformation requires some residual secondary structure to be present in the denatured state. %B Biopolymers %V 26 %P 937–62 %8 jun %G eng %U http://www.ncbi.nlm.nih.gov/pubmed/3607251 %R 10.1002/bip.360260613 %0 Journal Article %J Proceedings of the National Academy of Sciences of the United States of America %D 1986 %T Monte Carlo simulations on an equilibrium globular protein folding model %A Andrzej Koliński %A Jeffrey Skolnick %A Robert Yaris %K Models %K Protein Conformation %K Statistics as Topic %K Structural %K Structure-Activity Relationship %K Temperature %K Thermodynamics %X

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

%B Proceedings of the National Academy of Sciences of the United States of America %V 83 %P 7267–71 %8 oct %G eng %U http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=386697&tool=pmcentrez&rendertype=abstract