@article {Kamel2011, title = {Computational study of binding of epothilone A to β-tubulin}, journal = {Acta Biochimica Polonica}, volume = {58}, number = {2}, year = {2011}, month = {jan}, pages = {255{\textendash}60}, abstract = {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.}, keywords = {Animals, Binding Sites, Cattle, Computer Simulation, Epothilones, Epothilones: chemistry, Hydrogen Bonding, Models, Molecular, Protein Binding, Thermodynamics, Tubulin, Tubulin: chemistry}, issn = {1734-154X}, url = {http://www.ncbi.nlm.nih.gov/pubmed/21633729}, author = {Karol Kamel and Andrzej Koli{\'n}ski} } @proceedings {Steczkiewicz2011, title = {Human telomerase model shows the role of the TEN domain in advancing the double helix for the next polymerization step}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {108}, number = {23}, year = {2011}, month = {jun}, pages = {9443{\textendash}8}, abstract = {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.}, keywords = {Amino Acid, Amino Acid Sequence, Binding Sites, Binding Sites: genetics, Catalytic Domain, Computer Simulation, DNA, DNA: chemistry, DNA: genetics, DNA: metabolism, Humans, Kinetics, Models, Molecular, Molecular Sequence Data, Nucleic Acid Conformation, Nucleic Acid Heteroduplexes, Nucleic Acid Heteroduplexes: chemistry, Nucleic Acid Heteroduplexes: genetics, Nucleic Acid Heteroduplexes: metabolism, Polymerization, Protein Binding, Protein Structure, RNA, RNA: chemistry, RNA: genetics, RNA: metabolism, Secondary, Sequence Homology, Telomerase, Telomerase: chemistry, Telomerase: genetics, Telomerase: metabolism, Telomere, Telomere: chemistry, Telomere: genetics, Telomere: metabolism, Tertiary}, issn = {1091-6490}, doi = {10.1073/pnas.1015399108}, url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3111281\&tool=pmcentrez\&rendertype=abstract}, author = {Kamil Steczkiewicz and Michael T. Zimmermann and Mateusz Kurcinski and Benjamin A. Lewis and Drena Dobbs and Andrzej Kloczkowski and Robert L. Jernigan and Andrzej Koli{\'n}ski and Krzysztof Ginalski} } @article {Kurcinski2010, title = {Theoretical study of molecular mechanism of binding TRAP220 coactivator to Retinoid X Receptor alpha, activated by 9-cis retinoic acid}, journal = {The Journal of Steroid Biochemistry and Molecular Biology}, volume = {121}, number = {1-2}, year = {2010}, month = {jul}, pages = {124{\textendash}9}, publisher = {Elsevier Ltd}, abstract = {

Study on molecular mechanism of conformational reorientation of RXR-alpha ligand binding domain is presented. We employed CABS{\textendash}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.

}, keywords = {Binding Sites, Cell Nucleus, Cell Nucleus: metabolism, Computer Simulation, Crystallography, Humans, Ligands, Mediator Complex Subunit 1, Mediator Complex Subunit 1: metabolism, Models, Molecular, Molecular Conformation, Peptides, Peptides: chemistry, Protein Binding, Protein Structure, Retinoid X Receptor alpha, Retinoid X Receptor alpha: metabolism, Tertiary, Theoretical, Tretinoin, Tretinoin: metabolism, X-Ray, X-Ray: methods}, issn = {1879-1220}, doi = {10.1016/j.jsbmb.2010.03.086}, url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2906686\&tool=pmcentrez\&rendertype=abstract}, author = {Mateusz Kurcinski and Andrzej Koli{\'n}ski} } @article {Kloczkowski2009, title = {Distance matrix-based approach to protein structure prediction}, journal = {Journal of Structural and Functional Genomics}, volume = {10}, number = {1}, year = {2009}, month = {mar}, pages = {67{\textendash}81}, abstract = {

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){\textendash}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).

}, keywords = {Binding Sites, Computer Simulation, Databases, Models, Molecular, Principal Component Analysis, Protein, Protein Conformation, Proteins, Proteins: chemistry}, issn = {1570-0267}, doi = {10.1007/s10969-009-9062-2}, url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3018873\&tool=pmcentrez\&rendertype=abstract}, author = {Andrzej Kloczkowski and Robert L. Jernigan and Zhijun Wu and Guang Song and Lei Yang and Andrzej Koli{\'n}ski and Piotr Pokarowski} } @article {413, title = {On the remarkable mechanostability of scaffoldins and the mechanical clamp motif.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {106}, year = {2009}, month = {2009 Aug 18}, pages = {13791-6}, abstract = {Protein mechanostability is a fundamental biological property that can only be measured by single-molecule manipulation techniques. Such studies have unveiled a variety of highly mechanostable modules (mainly of the Ig-like, beta-sandwich type) in modular proteins subjected to mechanical stress from the cytoskeleton and the metazoan cell-cell interface. Their mechanostability is often attributed to a "mechanical clamp" of secondary structure (a patch of backbone hydrogen bonds) fastening their ends. Here we investigate the nanomechanics of scaffoldins, an important family of scaffolding proteins that assembles a variety of cellulases into the so-called cellulosome, a microbial extracellular nanomachine for cellulose adhesion and degradation. These proteins anchor the microbial cell to cellulose substrates, which makes their connecting region likely to be subjected to mechanical stress. By using single-molecule force spectroscopy based on atomic force microscopy, polyprotein engineering, and computer simulations, here we show that the cohesin I modules from the connecting region of cellulosome scaffoldins are the most robust mechanical proteins studied experimentally or predicted from the entire Protein Data Bank. The mechanostability of the cohesin modules studied correlates well with their mechanical kinetic stability but not with their thermal stability, and it is well predicted by computer simulations, even coarse-grained. This extraordinary mechanical stability is attributed to 2 mechanical clamps in tandem. Our findings provide the current upper limit of protein mechanostability and establish shear mechanical clamps as a general structural/functional motif widespread in proteins putatively subjected to mechanical stress. These data have important implications for the scaffoldin physiology and for protein design in biotechnology and nanotechnology.}, keywords = {Amino Acid Motifs, Biotechnology, Cellulose, Clostridium thermocellum, Computer Simulation, Databases, Protein, Kinetics, Microscopy, Atomic Force, Nanotechnology, Protein Conformation, Protein Engineering, Protein Folding, Protein Structure, Secondary, Proteins, Stress, Mechanical}, issn = {1091-6490}, doi = {10.1073/pnas.0813093106}, author = {Valbuena, Alejandro and Oroz, Javier and Herv{\'a}s, Rub{\'e}n and Vera, Andr{\'e}s Manuel and Rodr{\'\i}guez, David and Men{\'e}ndez, Margarita and Joanna I. Sulkowska and Cieplak, Marek and Carri{\'o}n-V{\'a}zquez, Mariano} } @article {294, title = {Structural changes of vitamin D receptor induced by 20-epi-1alpha,25-(OH)2D3: an insight from a computational analysis}, journal = {The Journal of Steroid Biochemistry and Molecular Biology}, volume = {113}, year = {2009}, month = {2009 Feb}, pages = {253-8}, abstract = {We employ a new computational tool CCOMP for the comparison of side chain (SC) conformations between crystal structures of homologous protein complexes. The program is applied to the vitamin D receptor (VDR) liganded with 1alpha,25-(OH)(2)D(3) (in 1DB1) or its 20-epi (in 1IE9) analog with an inverted C-20 configuration. This modification yields no detectable changes in the backbone configuration or ligand topology in the receptor binding cavity, yet it dramatically increases transcription, differentiation and antiproliferation activity of the VDR. We applied very stringent criteria during the comparison process. To eliminate errors arising from the different packing of investigated crystals and the thermal flexibility of atoms, we studied complexes belonging to the same space group, having a low R value (0.2) and a B-factor below 40 for compared residues. We find that 20-epi-1alpha,25-(OH)(2)D(3) changes side chain conformation of amino acids residing far away from direct ligand-VDR contacts. We further verify that a number of the reoriented residues were identified in mutational experiments as important for interaction with SRC-1, GRIP, TAFs co-activators and VDR-RXR heterodimerization. Thus, CCOMP analysis of protein complexes may be used for identifying amino acids that could serve as targets for genetic engineering, such as mutagenesis.}, keywords = {Animals, Bone Density Conservation Agents, Calcitriol, Computer Simulation, Crystallography, X-Ray, Drug Design, Humans, Ligands, Molecular Structure, Protein Structure, Tertiary, Receptors, Calcitriol, Reproducibility of Results, Software, Transcription, Genetic}, issn = {1879-1220}, doi = {10.1016/j.jsbmb.2009.01.007}, author = {Wanda Sicinska and Piotr Rotkiewicz} } @article {Latek2008, title = {Contact prediction in protein modeling: scoring, folding and refinement of coarse-grained models}, journal = {BMC Structural Biology}, volume = {8}, year = {2008}, month = {jan}, pages = {36}, abstract = {

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.

}, keywords = {Algorithms, Caspase 6, Caspase 6: chemistry, Caspase 6: genetics, Computer Simulation, Databases, Models, Molecular, Protein, Protein Folding, Proteins, Proteins: chemistry, Proteins: genetics}, issn = {1472-6807}, doi = {10.1186/1472-6807-8-36}, url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2527566\&tool=pmcentrez\&rendertype=abstract}, author = {Dorota Latek and Andrzej Koli{\'n}ski} } @article {Kmiecik2008, title = {Folding pathway of the b1 domain of protein G explored by multiscale modeling}, journal = {Biophysical Journal}, volume = {94}, number = {3}, year = {2008}, month = {feb}, pages = {726{\textendash}36}, publisher = {Elsevier}, abstract = {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.}, keywords = {Chemical, coarse-grained modeling, Computer Simulation, Models, Molecular, Molecular Dynamics Simulation, Nerve Tissue Proteins, Nerve Tissue Proteins: chemistry, Nerve Tissue Proteins: ultrastructure, Protein Conformation, protein dynamics, Protein Folding, Protein Structure, Tertiary}, issn = {1542-0086}, doi = {10.1529/biophysj.107.116095}, url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2186257\&tool=pmcentrez\&rendertype=abstract}, author = {Sebastian Kmiecik and Andrzej Koli{\'n}ski} } @article {Sen2008, title = {Predicting the complex structure and functional motions of the outer membrane transporter and signal transducer FecA}, journal = {Biophysical journal}, volume = {94}, number = {7}, year = {2008}, month = {apr}, pages = {2482{\textendash}91}, publisher = {Elsevier}, abstract = {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.}, keywords = {Cell Membrane, Cell Membrane: chemistry, Cell Surface, Cell Surface: chemistry, Cell Surface: ultrastructure, Chemical, Computer Simulation, Escherichia coli Proteins, Escherichia coli Proteins: chemistry, Escherichia coli Proteins: ultrastructure, Models, Molecular, Motion, Protein Conformation, Receptors}, isbn = {5152944294}, issn = {1542-0086}, doi = {10.1529/biophysj.107.116046}, url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2267147\&tool=pmcentrez\&rendertype=abstract}, author = {Taner Z. Sen and Margaret Kloster and Robert L. Jernigan and Andrzej Koli{\'n}ski and Janusz M. Bujnicki and Andrzej Kloczkowski} } @article {415, title = {Stabilizing effect of knots on proteins.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {105}, year = {2008}, month = {2008 Dec 16}, pages = {19714-9}, abstract = {Molecular dynamics studies within a coarse-grained, structure-based model were used on two similar proteins belonging to the transcarbamylase family to probe the effects of the knot in the native structure of a protein. The first protein, N-acetylornithine transcarbamylase, contains no knot, whereas human ormithine transcarbamylase contains a trefoil knot located deep within the sequence. In addition, we also analyzed a modified transferase with the knot removed by the appropriate change of a knot-making crossing of the protein chain. The studies of thermally and mechanically induced unfolding processes suggest a larger intrinsic stability of the protein with the knot.}, keywords = {Computer Simulation, Disulfides, Hot Temperature, Humans, Models, Chemical, Ornithine Carbamoyltransferase, Protein Folding, Protein Structure, Secondary, Stress, Mechanical}, issn = {1091-6490}, doi = {10.1073/pnas.0805468105}, author = {Joanna I. Sulkowska and Sulkowski, Piotr and Szymczak, P and Cieplak, Marek} } @article {419, title = {Stretching to understand proteins - a survey of the protein data bank.}, journal = {Biophys J}, volume = {94}, year = {2008}, month = {2008 Jan 1}, pages = {6-13}, abstract = {We make a survey of resistance of 7510 proteins to mechanical stretching at constant speed as studied within a coarse-grained molecular dynamics model. We correlate the maximum force of resistance with the native structure, predict proteins which should be especially strong, and identify the nature of their force clamps.}, keywords = {Computer Simulation, Databases, Protein, elasticity, Models, Chemical, Models, Molecular, Proteins, Sequence Analysis, Protein, Stress, Mechanical, Structure-Activity Relationship}, issn = {1542-0086}, doi = {10.1529/biophysj.107.105973}, author = {Joanna I. Sulkowska and Cieplak, Marek} } @article {Kmiecik2007a, title = {Characterization of protein-folding pathways by reduced-space modeling}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {104}, number = {30}, year = {2007}, month = {jul}, pages = {12330{\textendash}5}, abstract = {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.}, keywords = {Amino Acid Sequence, coarse-grained modeling, Computational Biology, Computer Simulation, Hydrophobic and Hydrophilic Interactions, Models, Molecular, Molecular Dynamics Simulation, Monte Carlo Method, Protein Denaturation, protein dynamics, Protein Folding, Protein Structure, Proteins, Proteins: chemistry, Proteins: metabolism, Temperature, Tertiary}, issn = {0027-8424}, doi = {10.1073/pnas.0702265104}, url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1941469\&tool=pmcentrez\&rendertype=abstract}, author = {Sebastian Kmiecik and Andrzej Koli{\'n}ski} } @article {Kolinski2007, title = {Comparative modeling without implicit sequence alignments}, journal = {Bioinformatics (Oxford, England)}, volume = {23}, number = {19}, year = {2007}, pages = {2522{\textendash}7}, abstract = {

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.

}, keywords = {Algorithms, Amino Acid Sequence, Chemical, Computer Simulation, Models, Molecular, Molecular Sequence Data, Protein, Protein Conformation, Protein: methods, Proteins, Proteins: chemistry, Proteins: ultrastructure, Sequence Alignment, Sequence Alignment: methods, Sequence Analysis}, issn = {1367-4811}, doi = {10.1093/bioinformatics/btm380}, url = {http://www.ncbi.nlm.nih.gov/pubmed/17660201}, author = {Andrzej Koli{\'n}ski and Dominik Gront} } @article {295, title = {Computational analysis of the active sites in binary and ternary complexes of the vitamin D receptor}, journal = {The Journal of Steroid Biochemistry and Molecular Biology}, volume = {103}, year = {2007}, month = {2007 Mar}, pages = {305-9}, abstract = {We have developed a program CCOMP that compares overlapping fragments of two protein complexes and identifies differently oriented amino acids. CCOMP initially performs a sequence alignment of the analyzed receptors, then superimposes the corresponding aligned residues, and finally calculates the root mean square deviation (RMSD) of individual atoms, every amino acid and the entire complex. Thus, amino acids important for functional differences between both complexes can be detected. Application of CCOMP to 1alpha,25-(OH)(2)D(3)-hVDR (1DB1) [Proc. Natl. Acad. Sci. U.S.A. 98 (2001) 5491] and 1alpha,25-(OH)(2)D(3)-rVDR-peptide (1RK3) [Biochemistry 43 (2004) 4101] complexes revealed that the peptide (KNHPMLMNLLKDN) mimicking a co-activator sequence significantly changes the side chain conformation of 35 amino acids. Four of these residues (K242, I256, K260, E416) actually contact the peptide, but all of them are essential for biological activity. Only two (L309 and L400) of the 35 differently oriented amino acids contact the ligand. Interestingly, when the peptide is present (1RK3) leucine 400 shifts closer (0.7A) to the vitamin D 26-methyl group. Applying the CCOMP and DSSP programs to binary and ternary VDR complexes also resulted in establishing that seven amino acids (I238, S252, I256, L413, L415, E416, V417) exhibit significant differences in solvent accessibility and are capable of interacting with co-activators.}, keywords = {Binding Sites, Biomimetic Materials, Computer Simulation, Models, Molecular, Peptides, Protein Binding, Protein Structure, Tertiary, Receptors, Calcitriol, Solvents}, issn = {0960-0760}, doi = {10.1016/j.jsbmb.2006.12.077}, author = {Wanda Sicinska and Piotr Rotkiewicz} } @article {Kurcinski2007a, title = {Hierarchical modeling of protein interactions}, journal = {Journal of Molecular Modeling}, volume = {13}, number = {6-7}, year = {2007}, month = {jul}, pages = {691{\textendash}698}, abstract = {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.}, keywords = {Algorithms, Amino Acid Sequence, Amino Acids, Amino Acids: analysis, Carbon, Carbon: chemistry, Computer Simulation, Crystallography, Hydrogen Bonding, Models, Molecular, Monte Carlo Method, Peptides, Peptides: chemistry, Peptides: metabolism, Protein Binding, Protein Conformation, Protein Structure, Proteins, Proteins: chemistry, Proteins: metabolism, Secondary, Stereoisomerism, Theoretical, X-Ray}, issn = {0948-5023}, doi = {10.1007/s00894-007-0177-8}, url = {http://www.ncbi.nlm.nih.gov/pubmed/17297609}, author = {Mateusz Kurcinski and Andrzej Koli{\'n}ski} } @article {Latek2007, title = {Protein structure prediction: combining de novo modeling with sparse experimental data}, journal = {Journal of Computational Chemistry}, volume = {28}, number = {10}, year = {2007}, month = {jul}, pages = {1668{\textendash}76}, abstract = {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.}, keywords = {Algorithms, Computer Simulation, Magnetic Resonance Spectroscopy, Models, Molecular, Protein Folding, Protein Structure, Proteins, Proteins: chemistry, Secondary, Software}, issn = {0192-8651}, doi = {10.1002/jcc.20657}, url = {http://www.ncbi.nlm.nih.gov/pubmed/17342709}, author = {Dorota Latek and Dariusz Ekonomiuk and Andrzej Koli{\'n}ski} } @article {Kmiecik2007, title = {Towards the high-resolution protein structure prediction. Fast refinement of reduced models with all-atom force field}, journal = {BMC Structural Biology}, volume = {7}, year = {2007}, month = {jan}, pages = {43}, abstract = {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. }, keywords = {Computer Simulation, Models, Molecular, Protein Structure, protein structure prediction, Proteins, Proteins: chemistry, Secondary, Software, Tertiary, Time Factors}, isbn = {1472680774}, issn = {1472-6807}, doi = {10.1186/1472-6807-7-43}, url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1933428\&tool=pmcentrez\&rendertype=abstract}, author = {Sebastian Kmiecik and Dominik Gront and Andrzej Koli{\'n}ski} } @article {Rutkowska2007, title = {Why do proteins divide into domains? Insights from lattice model simulations}, journal = {Biomacromolecules}, volume = {8}, year = {2007}, month = {nov}, pages = {3519{\textendash}24}, abstract = {

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.

}, keywords = {Computer Simulation, Models, Molecular, Polymers, Polymers: chemistry, Protein Structure, Proteins, Proteins: chemistry, Temperature, Tertiary}, issn = {1525-7797}, doi = {10.1021/bm7007718}, url = {http://www.ncbi.nlm.nih.gov/pubmed/17929971}, author = {Aleksandra Rutkowska and Andrzej Koli{\'n}ski} } @article {Gront2006, title = {BioShell{\textendash}a package of tools for structural biology computations}, journal = {Bioinformatics (Oxford, England)}, volume = {22}, number = {5}, year = {2006}, month = {mar}, pages = {621{\textendash}622}, abstract = {

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.

}, keywords = {Chemical, Computational Biology, Computational Biology: methods, Computer Simulation, Databases, Models, Protein, Protein: methods, Proteins, Proteins: analysis, Proteins: chemistry, Proteins: classification, Sequence Alignment, Sequence Alignment: methods, Sequence Analysis, Software}, issn = {1367-4803}, doi = {10.1093/bioinformatics/btk037}, url = {http://www.ncbi.nlm.nih.gov/pubmed/16407320}, author = {Dominik Gront and Andrzej Koli{\'n}ski} } @article {254, title = {Clustering as a supporting tool for structural drug design}, journal = {Acta Poloniae Pharmaceutica. Drug Research}, volume = {63}, year = {2006}, month = {2006 Sep-Oct}, pages = {436-8}, keywords = {Cluster Analysis, Computer Simulation, Drug Design, Ligands, Models, Molecular, Molecular Structure, Protein Binding}, issn = {0001-6837}, author = {Dominik Gront and Mateusz Kurcinski and Andrzej Koli{\'n}ski} } @article {Kmiecik2006, title = {Denatured proteins and early folding intermediates simulated in a reduced conformational space}, journal = {Acta Biochimica Polonica}, volume = {53}, number = {1}, year = {2006}, month = {jan}, pages = {131{\textendash}143}, abstract = {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{\textquoteright}s paradox.}, keywords = {Animals, Biophysics, Biophysics: methods, Chymotrypsin, Chymotrypsin: antagonists \& inhibitors, Chymotrypsin: chemistry, Computer Simulation, Cytochromes c, Cytochromes c: chemistry, Models, Molecular, Molecular Conformation, Monte Carlo Method, Protein Conformation, Protein Denaturation, Protein Folding, Ribonucleases, Ribonucleases: chemistry, src Homology Domains, Statistical}, issn = {0001-527X}, url = {http://www.ncbi.nlm.nih.gov/pubmed/16365636}, author = {Sebastian Kmiecik and Mateusz Kurcinski and Aleksandra Rutkowska and Dominik Gront and Andrzej Koli{\'n}ski} } @article {Kolinski2005, title = {Generalized protein structure prediction based on combination of fold-recognition with de novo folding and evaluation of models}, journal = {Proteins}, volume = {61 Suppl. 7}, number = {April}, year = {2005}, month = {jan}, pages = {84{\textendash}90}, abstract = {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{\textquoteright}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.}, keywords = {Algorithms, Computational Biology, Computational Biology: methods, Computer Simulation, Computers, Data Interpretation, Databases, Dimerization, Models, Molecular, Monte Carlo Method, Protein, Protein Conformation, Protein Folding, Protein Structure, Proteomics, Proteomics: methods, Reproducibility of Results, Secondary, Sequence Alignment, Software, Statistical, Tertiary}, issn = {1097-0134}, doi = {10.1002/prot.20723}, url = {http://www.ncbi.nlm.nih.gov/pubmed/16187348}, author = {Andrzej Koli{\'n}ski and Janusz M. Bujnicki} } @article {Gront2005, title = {HCPM{\textendash}program for hierarchical clustering of protein models}, journal = {Bioinformatics}, volume = {21}, number = {14}, year = {2005}, pages = {3179{\textendash}80}, abstract = {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.}, keywords = {Algorithms, Chemical, Cluster Analysis, Computer Simulation, Internet, Models, Molecular, Protein, Protein: methods, Proteins, Proteins: analysis, Proteins: chemistry, Sequence Alignment, Sequence Alignment: methods, Sequence Analysis, Software, User-Computer Interface}, issn = {1367-4803}, doi = {10.1093/bioinformatics/bti450}, url = {http://www.ncbi.nlm.nih.gov/pubmed/15840705}, author = {Dominik Gront and Andrzej Koli{\'n}ski} } @article {Pokarowski2005a, title = {A minimal proteinlike lattice model: an alpha-helix motif}, journal = {The Journal of Chemical Physics}, volume = {122}, number = {21}, year = {2005}, month = {jun}, pages = {214915}, abstract = {A simple protein model of a four-helix bundle motif on a face-centered cubic lattice has been studied. Total energy of a conformation includes attractive interactions between hydrophobic residues, repulsive interactions between hydrophobic and polar residues, and a potential that favors helical turns. Using replica exchange Monte Carlo simulations we have estimated a set of parameters for which the native structure is a global minimum of conformational energy. Then we have shown that all the above types of interactions are necessary to guarantee the cooperativity of folding transition and to satisfy the thermodynamic hypothesis.}, keywords = {Algorithms, Computer Simulation, Hydrophobic and Hydrophilic Interactions, Protein Folding, Protein Structure, Proteins, Proteins: chemistry, Secondary, Thermodynamics}, issn = {0021-9606}, doi = {10.1063/1.1924601}, url = {http://www.ncbi.nlm.nih.gov/pubmed/15974798}, author = {Piotr Pokarowski and Karol Droste and Andrzej Koli{\'n}ski} } @article {Gront2005a, title = {A new approach to prediction of short-range conformational propensities in proteins}, journal = {Bioinformatics (Oxford, England)}, volume = {21}, number = {7}, year = {2005}, pages = {981{\textendash}987}, abstract = {

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.

}, keywords = {Algorithms, Amino Acid, Artificial Intelligence, Chemical, Computer Simulation, Databases, Gas Chromatography-Mass Spectrometry, Gas Chromatography-Mass Spectrometry: methods, Models, Protein, Protein Conformation, Protein: methods, Proteins, Proteins: analysis, Proteins: chemistry, Sequence Alignment, Sequence Alignment: methods, Sequence Analysis, Sequence Homology, Structure-Activity Relationship}, issn = {1367-4803}, doi = {10.1093/bioinformatics/bti080}, url = {http://www.ncbi.nlm.nih.gov/pubmed/15509604}, author = {Dominik Gront and Andrzej Koli{\'n}ski} } @article {Ekonomiuk2005, title = {Protein modeling with reduced representation: statistical potentials and protein folding mechanism}, journal = {Acta Biochimica Polonica}, volume = {52}, number = {4}, year = {2005}, month = {jan}, pages = {741{\textendash}8}, abstract = {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.}, keywords = {Biophysical Phenomena, Biophysics, Computer Simulation, Models, Molecular, Monte Carlo Method, Protein Conformation, Protein Folding, Proteins, Proteins: chemistry, Proteins: metabolism}, issn = {0001-527X}, url = {http://www.ncbi.nlm.nih.gov/pubmed/15933762}, author = {Dariusz Ekonomiuk and Marcin Kielbasinski and Andrzej Koli{\'n}ski} } @article {Gront2005b, title = {Protein structure prediction by tempering spatial constraints}, journal = {Journal of Computer-Aided Molecular Design}, volume = {19}, number = {8}, year = {2005}, month = {aug}, pages = {603{\textendash}8}, abstract = {The probability to predict correctly a protein structure can be enhanced through introduction of spatial constraints - either from NMR experiments or from homologous structures. However, the additional constraints lead often to new local energy minima and worse sampling efficiency in simulations. In this work, we present a new parallel tempering variant that alleviates the energy barriers resulting from spatial constraints and therefore yields to an enhanced sampling in structure prediction simulations.}, keywords = {Algorithms, Computer Simulation, Monte Carlo Method, Protein Conformation, Temperature}, isbn = {1082200590160}, issn = {0920-654X}, doi = {10.1007/s10822-005-9016-0}, url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1473033\&tool=pmcentrez\&rendertype=abstract}, author = {Dominik Gront and Andrzej Koli{\'n}ski and Ulrich H. E. Hansmann} } @article {Maolepsza2005, title = {Theoretical model of prion propagation: a misfolded protein induces misfolding}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {102}, number = {22}, year = {2005}, month = {may}, pages = {7835{\textendash}40}, abstract = {There is a hypothesis that dangerous diseases such as bovine spongiform encephalopathy, Creutzfeldt-Jakob, Alzheimer{\textquoteright}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.}, keywords = {Amino Acid Sequence, Amino Acids, Amino Acids: metabolism, Computer Simulation, Models, Molecular, Monte Carlo Method, Prions, Prions: metabolism, Protein Conformation, Protein Folding, Theoretical}, isbn = {0409389102}, issn = {0027-8424}, doi = {10.1073/pnas.0409389102}, url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1142357\&tool=pmcentrez\&rendertype=abstract}, author = {Edyta Ma{\l}olepsza and Michal Boniecki and Andrzej Koli{\'n}ski and Lucjan Piela} } @article {421, title = {Thermal unfolding of proteins.}, journal = {J Chem Phys}, volume = {123}, year = {2005}, month = {2005 Nov 15}, pages = {194908}, abstract = {Thermal unfolding of proteins is compared to folding and mechanical stretching in a simple topology-based dynamical model. We define the unfolding time and demonstrate its low-temperature divergence. Below a characteristic temperature, contacts break at separate time scales and unfolding proceeds approximately in a way reverse to folding. Features in these scenarios agree with experiments and atomic simulations on titin.}, keywords = {Chemistry, Physical, Computer Simulation, Connectin, Kinetics, Models, Molecular, Molecular Conformation, Muscle Proteins, Protein Conformation, Protein Denaturation, Protein Folding, Protein Kinases, Protein Structure, Secondary, Proteins, Temperature, Time Factors}, issn = {0021-9606}, doi = {10.1063/1.2121668}, author = {Cieplak, Marek and Joanna I. Sulkowska} } @article {Pokarowski2003, title = {A minimal physically realistic protein-like lattice model: designing an energy landscape that ensures all-or-none folding to a unique native state}, journal = {Biophysical Journal}, volume = {84}, number = {3}, year = {2003}, month = {mar}, pages = {1518{\textendash}26}, abstract = {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.}, keywords = {Amino Acid Motifs, Computer Simulation, Crystallography, Crystallography: methods, Energy Transfer, Entropy, Mechanical, Models, Molecular, Monte Carlo Method, Peptides, Peptides: chemistry, Protein Conformation, Protein Folding, Protein Structure, Proteins, Proteins: chemistry, Static Electricity, Stress, Tertiary}, issn = {0006-3495}, doi = {10.1016/S0006-3495(03)74964-9}, url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1302725\&tool=pmcentrez\&rendertype=abstract}, author = {Piotr Pokarowski and Andrzej Koli{\'n}ski and Jeffrey Skolnick} } @article {300, title = {Solvent polarity and hydrogen-bonding effects on the nitrogen NMR shieldings of N-nitrosamines and DFT calculations of the shieldings of C-, N-, and O-nitroso systems}, journal = {Journal of Magnetic Resonance}, volume = {164}, year = {2003}, month = {2003 Oct}, pages = {212-9}, abstract = {High-precision nitrogen NMR shieldings, bulk susceptibility corrected, are reported for dimethyl-N-nitrosamine (I) and diethyl-N-nitrosamine (II) in a variety of solvents which represent a wide range of solvent properties from the point of view of polarity as well as hydrogen bond donor and acceptor strength. The observed range of solvent-induced nitrogen shielding variations of (I) and (II) is significant for the amino-type nitrogens, up to about 16 ppm, and originates essentially from the deshielding effect of the increasing polarity of solvent. On the other side, the nitroso nitrogen shieldings reveal an even stronger response to solvent effects, within about 20 ppm, but in this case the increasing polarity and hydrogen bond donor strength of solvent produce enhanced shielding. DFT quantum-mechanical calculations using the GIAO/B3PW91/6-311++G** approach and geometry optimizations employing the same basis set and hybrid density functionals show an excellent correlation with the experimental data on C-, N-, and O-nitroso moieties and reproduce not only major changes but also most of the subtle variations in the experimental nitrogen shieldings of the nitroso systems as a whole. A combination of the calculations involving the corresponding N and O-protonated species and the trends observed in the solvent-induced nitrogen shielding variations shows clearly that the prime acceptor site for hydrogen bonding is the nitroso oxygen atom.}, keywords = {Algorithms, Binding Sites, Carbon, Computer Simulation, Hydrogen Bonding, Macromolecular Substances, Magnetic Resonance Spectroscopy, Models, Molecular, Molecular Conformation, Molecular Structure, Nitrogen, Nitrogen Isotopes, Nitrosamines, Nitroso Compounds, Oxygen, solutions, Solvents}, issn = {1090-7807}, author = {Michal Witanowski and Zenobia Biedrzycka and Wanda Sicinska and Zbigniew Grabowski} } @article {Zhang2003, title = {TOUCHSTONE II: a new approach to ab initio protein structure prediction}, journal = {Biophysical Journal}, volume = {85}, number = {2}, year = {2003}, pages = {1145{\textendash}64}, abstract = {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.}, keywords = {Algorithms, Amino Acid Sequence, Computer Simulation, Crystallography, Crystallography: methods, Energy Transfer, Models, Molecular, Molecular Sequence Data, Protein, Protein Conformation, Protein Folding, Protein Structure, Protein: methods, Proteins, Proteins: chemistry, Secondary, Sequence Analysis, Software, Static Electricity, Statistical}, issn = {0006-3495}, doi = {10.1016/S0006-3495(03)74551-2}, url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1303233\&tool=pmcentrez\&rendertype=abstract}, author = {Yang Zhang and Andrzej Koli{\'n}ski and Jeffrey Skolnick} } @article {Sikorski2002, title = {Computer simulations of protein folding with a small number of distance restraints}, journal = {Acta Biochimica Polonica}, volume = {49}, number = {3}, year = {2002}, month = {jan}, pages = {683{\textendash}692}, abstract = {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.}, keywords = {Algorithms, Amino Acids, Amino Acids: chemistry, Chemical, Computer Simulation, Hydrogen Bonding, Models, Molecular, Monte Carlo Method, Nerve Tissue Proteins, Nerve Tissue Proteins: chemistry, Plastocyanin, Plastocyanin: chemistry, Protein Conformation, Protein Folding, Protein Kinases, Thermodynamics}, issn = {0001-527X}, doi = {024903683}, url = {http://www.ncbi.nlm.nih.gov/pubmed/12422238}, author = {Andrzej Sikorski and Andrzej Koli{\'n}ski and Jeffrey Skolnick} } @article {Kolinski2001, title = {Generalized comparative modeling (GENECOMP): a combination of sequence comparison, threading, and lattice modeling for protein structure prediction and refinement}, journal = {Proteins}, volume = {44}, number = {2}, year = {2001}, month = {aug}, pages = {133{\textendash}149}, abstract = {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.}, keywords = {Algorithms, Chemical, Combinatorial Chemistry Techniques, Combinatorial Chemistry Techniques: methods, Computational Biology, Computational Biology: methods, Computer Simulation, Databases, Factual, Models, Molecular, Monte Carlo Method, Protein Folding, Proteins, Proteins: chemistry, Sequence Alignment, Sequence Alignment: methods}, issn = {0887-3585}, url = {http://www.ncbi.nlm.nih.gov/pubmed/11391776}, author = {Andrzej Koli{\'n}ski and Marcos Betancourt and Daisuke Kihara and Piotr Rotkiewicz and Jeffrey Skolnick} } @article {Kihara2001, title = {TOUCHSTONE: an ab initio protein structure prediction method that uses threading-based tertiary restraints}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {98}, number = {18}, year = {2001}, month = {aug}, pages = {10125{\textendash}30}, abstract = {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.}, keywords = {Algorithms, Computer Simulation, Models, Molecular, Monte Carlo Method, Protein Folding, Protein Structure, Proteins, Proteins: chemistry, Tertiary}, issn = {0027-8424}, doi = {10.1073/pnas.181328398}, url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=56926\&tool=pmcentrez\&rendertype=abstract}, author = {Daisuke Kihara and Hui Lu and Andrzej Koli{\'n}ski and Jeffrey Skolnick} } @article {Sikorski2000, title = {Computer simulations of the properties of the alpha2, alpha2C, and alpha2D de novo designed helical proteins}, journal = {Proteins}, volume = {38}, number = {1}, year = {2000}, month = {jan}, pages = {17{\textendash}28}, abstract = {Reduced lattice models of the three de novo designed helical proteins alpha2, alpha2C, and alpha2D were studied. Low temperature stable folds were obtained for all three proteins. In all cases, the lowest energy folds were four-helix bundles. The folding pathway is qualitatively the same for all proteins studied. The energies of various topologies are similar, especially for the alpha2 polypeptide. The simulated crossover from molten globule to native-like behavior is very similar to that seen in experimental studies. Simulations on a reduced protein model reproduce most of the experimental properties of the alpha2, alpha2C, and alpha2D proteins. Stable four-helix bundle structures were obtained, with increasing native-like behavior on-going from alpha2 to alpha2D that mimics experiment.}, keywords = {Amino Acid Sequence, Computer Simulation, Drug Design, Molecular Sequence Data, Protein Folding, Protein Structure, Proteins, Proteins: chemistry, Secondary, Thermodynamics}, issn = {0887-3585}, url = {http://www.ncbi.nlm.nih.gov/pubmed/10651035}, author = {Andrzej Sikorski and Andrzej Koli{\'n}ski and Jeffrey Skolnick} } @article {Skolnick2000, title = {Structural genomics and its importance for gene function analysis}, journal = {Nature Biotechnology}, volume = {18}, number = {3}, year = {2000}, month = {mar}, pages = {283{\textendash}287}, abstract = {Structural genomics projects aim to solve the experimental structures of all possible protein folds. Such projects entail a conceptual shift from traditional structural biology in which structural information is obtained on known proteins to one in which the structure of a protein is determined first and the function assigned only later. Whereas the goal of converting protein structure into function can be accomplished by traditional sequence motif-based approaches, recent studies have shown that assignment of a protein{\textquoteright}s biochemical function can also be achieved by scanning its structure for a match to the geometry and chemical identity of a known active site. Importantly, this approach can use low-resolution structures provided by contemporary structure prediction methods. When applied to genomes, structural information (either experimental or predicted) is likely to play an important role in high-throughput function assignment.}, keywords = {Animals, Computer Simulation, Databases, Evolution, Factual, Genome, Humans, Internet, Molecular, Molecular Biology, Molecular Biology: methods, Protein Folding, Structure-Activity Relationship}, issn = {1087-0156}, doi = {10.1038/73723}, url = {http://www.ncbi.nlm.nih.gov/pubmed/10700142}, author = {Jeffrey Skolnick and Jacquelyn S. Fetrow and Andrzej Koli{\'n}ski} } @article {Mohanty1999, title = {De novo simulations of the folding thermodynamics of the GCN4 leucine zipper}, journal = {Biophysical Journal}, volume = {77}, number = {1}, year = {1999}, month = {jul}, pages = {54{\textendash}69}, abstract = {Entropy Sampling Monte Carlo (ESMC) simulations were carried out to study the thermodynamics of the folding transition in the GCN4 leucine zipper (GCN4-lz) in the context of a reduced model. Using the calculated partition functions for the monomer and dimer, and taking into account the equilibrium between the monomer and dimer, the average helix content of the GCN4-lz was computed over a range of temperatures and chain concentrations. The predicted helix contents for the native and denatured states of GCN4-lz agree with the experimental values. Similar to experimental results, our helix content versus temperature curves show a small linear decline in helix content with an increase in temperature in the native region. This is followed by a sharp transition to the denatured state. van{\textquoteright}t Hoff analysis of the helix content versus temperature curves indicates that the folding transition can be described using a two-state model. This indicates that knowledge-based potentials can be used to describe the properties of the folded and unfolded states of proteins.}, keywords = {Computer Simulation, Dimerization, DNA-Binding Proteins, Fungal Proteins, Fungal Proteins: chemistry, Leucine Zippers, Monte Carlo Method, Protein Conformation, Protein Denaturation, Protein Folding, Protein Kinases, Protein Kinases: chemistry, Protein Structure, Saccharomyces cerevisiae Proteins, Secondary, Temperature, Thermodynamics}, isbn = {6197848821}, issn = {0006-3495}, doi = {10.1016/S0006-3495(99)76872-4}, url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1300312\&tool=pmcentrez\&rendertype=abstract}, author = {Debasisa Mohanty and Andrzej Koli{\'n}ski and Jeffrey Skolnick} } @article {Kolinski1999a, title = {A method for the improvement of threading-based protein models}, journal = {Proteins}, volume = {37}, number = {4}, year = {1999}, month = {dec}, pages = {592{\textendash}610}, abstract = {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{\textquoteright}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.}, keywords = {Amino Acid Sequence, Computer Simulation, Evaluation Studies as Topic, Methods, Models, Molecular, Molecular Sequence Data, Protein Conformation, Protein Structure, Proteins, Proteins: chemistry, Secondary, Sequence Alignment, Software Design}, issn = {0887-3585}, url = {http://www.ncbi.nlm.nih.gov/pubmed/10651275}, author = {Andrzej Koli{\'n}ski and Piotr Rotkiewicz and Bartosz Ilkowski and Jeffrey Skolnick} } @article {Kolinski1998, title = {Assembly of protein structure from sparse experimental data: an efficient Monte Carlo model}, journal = {Proteins}, volume = {32}, number = {4}, year = {1998}, month = {sep}, pages = {475{\textendash}494}, abstract = {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.}, keywords = {Algorithms, Computer Simulation, Models, Molecular, Monte Carlo Method, Protein Conformation, Protein Folding, Protein Structure, Secondary, Tertiary}, issn = {0887-3585}, url = {http://www.ncbi.nlm.nih.gov/pubmed/9726417}, author = {Andrzej Koli{\'n}ski and Jeffrey Skolnick} } @article {Sikorski1998, title = {Computer simulations of de novo designed helical proteins}, journal = {Biophysical Journal}, volume = {75}, number = {1}, year = {1998}, month = {jul}, pages = {92{\textendash}105}, abstract = {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.}, keywords = {Amino Acid Sequence, Biophysical Phenomena, Biophysics, Computer Simulation, Dimerization, Drug Design, Hydrogen Bonding, Models, Molecular, Molecular Sequence Data, Monte Carlo Method, Protein Conformation, Protein Folding, Protein Structure, Proteins, Proteins: chemistry, Secondary, Thermodynamics}, issn = {0006-3495}, doi = {10.1016/S0006-3495(98)77497-1}, url = {http://www.ncbi.nlm.nih.gov/pubmed/10651035}, author = {Andrzej Sikorski and Andrzej Koli{\'n}ski and Jeffrey Skolnick} } @article {Skolnick1997, title = {MONSSTER: a method for folding globular proteins with a small number of distance restraints}, journal = {Journal of Molecular Biology}, volume = {265}, number = {2}, year = {1997}, month = {jan}, pages = {217{\textendash}241}, abstract = {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.}, keywords = {Algorithms, Aprotinin, Aprotinin: chemistry, Bacterial Proteins, Bacterial Proteins: chemistry, Computer Graphics, Computer Simulation, Flavodoxin, Flavodoxin: chemistry, Models, Molecular, Myoglobin, Myoglobin: chemistry, Plastocyanin, Plastocyanin: chemistry, Protein Conformation, Protein Folding, Protein Structure, Secondary, Tertiary, Thioredoxins, Thioredoxins: chemistry}, issn = {0022-2836}, doi = {10.1006/jmbi.1996.0720}, url = {http://www.ncbi.nlm.nih.gov/pubmed/9020984}, author = {Jeffrey Skolnick and Andrzej Koli{\'n}ski and Angel. R. Ortiz} } @article {Olszewski1996, title = {Does a backwardly read protein sequence have a unique native state?}, journal = {Protein Engineering}, volume = {9}, number = {1}, year = {1996}, month = {jan}, pages = {5{\textendash}14}, abstract = {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.}, keywords = {Amino Acid Sequence, Computer Simulation, Models, Molecular, Molecular Sequence Data, Monte Carlo Method, Protein Conformation, Protein Engineering, Protein Folding, Protein Structure, Secondary, Staphylococcal Protein A, Staphylococcal Protein A: chemistry, Tertiary}, issn = {0269-2139}, url = {http://www.ncbi.nlm.nih.gov/pubmed/9053902}, author = {Krzysztof A. Olszewski and Andrzej Koli{\'n}ski and Jeffrey Skolnick} } @article {Olszewski1996a, title = {Folding simulations and computer redesign of protein A three-helix bundle motifs}, journal = {Proteins}, volume = {25}, number = {3}, year = {1996}, month = {jul}, pages = {286{\textendash}299}, abstract = {In solution, the B domain of protein A from Staphylococcus aureus (B domain) possesses a three-helix bundle structure. This simple motif has been previously reproduced by Kolinski and Skolnick (Proteins 18: 353-366, 1994) using a reduced representation lattice model of proteins with a statistical interaction scheme. In this paper, an improved version of the potential has been used, and the robustness of this result has been tested by folding from the random state a set of three-helix bundle proteins that are highly homologous to the B domain of protein A. Furthermore, an attempt to redesign the B domain native structure to its topological mirror image fold has been made by multiple mutations of the hydrophobic core and the turn region between helices I and II. A sieve method for scanning a large set of mutations to search for this desired property has been proposed. It has been shown that mutations of native B domain hydrophobic core do not introduce significant changes in the protein motif. Mutations in the turn region were also very conservative; nevertheless, a few mutants acquired the desired topological mirror image motif. A set of all atom models of the most probable mutant was reconstructed from the reduced models and refined using a molecular dynamics algorithm in the presence of water. The packing of all atom structures obtained corroborates the lattice model results. We conclude that the change in the handedness of the turn induced by the mutations, augmented by the repacking of hydrophobic core and the additional burial of the second helix N-cap side chain, are responsible for the predicted preferential adoption of the mirror image structure.}, keywords = {Computer Simulation, Monte Carlo Method, Mutation, Protein Conformation, Protein Folding, Staphylococcal Protein A, Staphylococcal Protein A: chemistry}, issn = {0887-3585}, doi = {10.1002/(SICI)1097-0134(199607)25:3\<286::AID-PROT2\>3.0.CO;2-E}, url = {http://www.ncbi.nlm.nih.gov/pubmed/8844865}, author = {Krzysztof A. Olszewski and Andrzej Koli{\'n}ski and Jeffrey Skolnick} } @article {Kolinski1996, title = {On the origin of the cooperativity of protein folding: implications from model simulations}, journal = {Proteins}, volume = {26}, number = {3}, year = {1996}, month = {nov}, pages = {271{\textendash}287}, abstract = {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.}, keywords = {Amino Acids, Amino Acids: chemistry, Chemical, Computer Simulation, Models, Molecular, Protein Conformation, Protein Folding, Thermodynamics}, isbn = {1028610297}, issn = {0887-3585}, doi = {10.1002/(SICI)1097-0134(199611)26:3<271::AID-PROT4>3.0.CO;2-H}, url = {http://www.ncbi.nlm.nih.gov/pubmed/8953649}, author = {Andrzej Koli{\'n}ski and Wojciech Galazka and Jeffrey Skolnick} } @article {Vieth1995, title = {Prediction of quaternary structure of coiled coils. Application to mutants of the GCN4 leucine zipper}, journal = {Journal of Molecular Biology}, volume = {251}, number = {3}, year = {1995}, month = {aug}, pages = {448{\textendash}67}, abstract = {Using a simplified protein model, the equilibrium between different oligomeric species of the wild-type GCN4 leucine zipper and seven of its mutants have been predicted. Over the entire experimental concentration range, agreement with experiment is found in five cases, while in two cases agreement is found over a portion of the concentration range. These studies demonstrate a methodology for predicting coiled coil quaternary structure and allow for the dissection of the interactions responsible for the global fold. In agreement with the conclusion of Harbury et al., the results of the simulations indicate that the pattern of hydrophobic and hydrophilic residues alone is insufficient to define a protein{\textquoteright}s three-dimensional structure. In addition, these simulations indicate that the degree of chain association is determined by the balance between specific side-chain packing preferences and the entropy reduction associated with side-chain burial in higher-order multimers.}, keywords = {Computer Simulation, DNA-Binding Proteins, Fungal Proteins, Fungal Proteins: chemistry, Hydrogen Bonding, Leucine Zippers, Monte Carlo Method, Mutation, Protein Conformation, Protein Folding, Protein Kinases, Protein Kinases: chemistry, Saccharomyces cerevisiae Proteins, Thermodynamics}, issn = {0022-2836}, doi = {10.1006/jmbi.1995.0447}, url = {http://www.ncbi.nlm.nih.gov/pubmed/7650742}, author = {Michal Vieth and Andrzej Koli{\'n}ski and Charles L. Brooks III and Jeffrey Skolnick} } @article {287, title = {Monte Carlo simulations of protein folding. I. Lattice model and interaction scheme}, journal = {Proteins}, volume = {18}, year = {1994}, month = {1994 Apr}, pages = {338-52}, abstract = {A new hierarchical method for the simulation of the protein folding process and the de novo prediction of protein three-dimensional structure is proposed. The reduced representation of the protein alpha-carbon backbone employs lattice discretizations of increasing geometrical resolution and a single ball representation of side chain rotamers. In particular, coarser and finer lattice backbone descriptions are used. The coarser (finer) lattice represents C alpha traces of native proteins with an accuracy of 1.0 (0.7) A rms. Folding is simulated by means of very fast Monte Carlo lattice dynamics. The potential of mean force, predominantly of statistical origin, contains several novel terms that facilitate the cooperative assembly of secondary structure elements and the cooperative packing of the side chains. Particular contributions to the interaction scheme are discussed in detail. In the accompanying paper (Kolinski, A., Skolnick, J. Monte Carlo simulation of protein folding. II. Application to protein A, ROP, and crambin. Proteins 18:353-366, 1994), the method is applied to three small globular proteins.}, keywords = {Amino Acid Sequence, Amino Acids, Computer Simulation, Hydrogen Bonding, Models, Chemical, Models, Molecular, Models, Theoretical, Molecular Sequence Data, Monte Carlo Method, Protein Folding, Protein Structure, Tertiary}, issn = {0887-3585}, doi = {10.1002/prot.340180405}, author = {Andrzej Koli{\'n}ski and Jeffrey Skolnick} }