@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 {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 {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 {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 {Boniecki2003, title = {Protein fragment reconstruction using various modeling techniques}, journal = {Journal of Computer-Aided Molecular Design}, volume = {17}, number = {11}, year = {2003}, month = {nov}, pages = {725{\textendash}38}, abstract = {Recently developed reduced models of proteins with knowledge-based force fields have been applied to a specific case of comparative modeling. From twenty high resolution protein structures of various structural classes, significant fragments of their chains have been removed and treated as unknown. The remaining portions of the structures were treated as fixed - i.e., as templates with an exact alignment. Then, the missed fragments were reconstructed using several modeling tools. These included three reduced types of protein models: the lattice SICHO (Side Chain Only) model, the lattice CABS (Calpha + Cbeta + Side group) model and an off-lattice model similar to the CABS model and called REFINER. The obtained reduced models were compared with more standard comparative modeling tools such as MODELLER and the SWISS-MODEL server. The reduced model results are qualitatively better for the higher resolution lattice models, clearly suggesting that these are now mature, competitive and complementary (in the range of sparse alignments) to the classical tools of comparative modeling. Comparison between the various reduced models strongly suggests that the essential ingredient for the sucessful and accurate modeling of protein structures is not the representation of conformational space (lattice, off-lattice, all-atom) but, rather, the specificity of the force fields used and, perhaps, the sampling techniques employed. These conclusions are encouraging for the future application of the fast reduced models in comparative modeling on a genomic scale.}, keywords = {Amino Acid Sequence, Binding Sites, Hydrogen Bonding, Models, Molecular, Peptide Fragments, Peptide Fragments: chemistry, Protein Conformation, Protein Structure, Proteins, Proteins: chemistry, Secondary}, issn = {0920-654X}, url = {http://www.ncbi.nlm.nih.gov/pubmed/15072433}, author = {Michal Boniecki and Piotr Rotkiewicz and Jeffrey Skolnick and Andrzej Koli{\'n}ski} } @article {Kolinski2003, title = {A simple lattice model that exhibits a protein-like cooperative all-or-none folding transition}, journal = {Biopolymers}, volume = {69}, number = {3}, year = {2003}, month = {jul}, pages = {399{\textendash}405}, abstract = {In a recent paper (D. Gront et al., Journal of Chemical Physics, Vol. 115, pp. 1569, 2001) we applied a simple combination of the Replica Exchange Monte Carlo and the Histogram methods in the computational studies of a simplified protein lattice model containing hydrophobic and polar units and sequence-dependent local stiffness. A well-defined, relatively complex Greek-key topology, ground (native) conformations was found; however, the cooperativity of the folding transition was very low. Here we describe a modified minimal model of the same Greek-key motif for which the folding transition is very cooperative and has all the features of the "all-or-none" transition typical of real globular proteins. It is demonstrated that the all-or-none transition arises from the interplay between local stiffness and properly defined tertiary interactions. The tertiary interactions are directional, mimicking the packing preferences seen in proteins. The model properties are compared with other minimal protein-like models, and we argue that the model presented here captures essential physics of protein folding (structurally well-defined protein-like native conformation and cooperative all-or-none folding transition).}, keywords = {Biopolymers, Biopolymers: chemistry, Biopolymers: metabolism, Chemical, Models, Molecular, Monte Carlo Method, Protein Folding, Protein Structure, Proteins, Proteins: chemistry, Proteins: metabolism, Secondary, Thermodynamics}, issn = {0006-3525}, doi = {10.1002/bip.10385}, url = {http://www.ncbi.nlm.nih.gov/pubmed/12833266}, author = {Andrzej Koli{\'n}ski and Dominik Gront and Piotr Pokarowski and Jeffrey Skolnick} } @article {Skolnick2003, title = {TOUCHSTONE: a unified approach to protein structure prediction.}, journal = {Proteins}, volume = {CASP Suppl}, number = {May}, year = {2003}, month = {jan}, pages = {469{\textendash}79}, abstract = {We have applied the TOUCHSTONE structure prediction algorithm that spans the range from homology modeling to ab initio folding to all protein targets in CASP5. Using our threading algorithm PROSPECTOR that does not utilize input from metaservers, one threads against a representative set of PDB templates. If a template is significantly hit, Generalized Comparative Modeling designed to span the range from closely to distantly related proteins from the template is done. This involves freezing the aligned regions and relaxing the remaining structure to accommodate insertions or deletions with respect to the template. For all targets, consensus predicted side chain contacts from at least weakly threading templates are pooled and incorporated into ab initio folding. Often, TOUCHSTONE performs well in the CM to FR categories, with PROSPECTOR showing significant ability to identify analogous templates. When ab initio folding is done, frequently the best models are closer to the native state than the initial template. Among the particularly good predictions are T0130 in the CM/FR category, T0138 in the FR(H) category, T0135 in the FR(A) category, T0170 in the FR/NF category and T0181 in the NF category. Improvements in the approach are needed in the FR/NF and NF categories. Nevertheless, TOUCHSTONE was one of the best performing algorithms over all categories in CASP5.}, keywords = {Algorithms, Models, Molecular, Protein Conformation, Protein Structure, Proteins, Proteins: chemistry, Secondary, Tertiary}, issn = {1097-0134}, doi = {10.1002/prot.10551}, url = {http://www.ncbi.nlm.nih.gov/pubmed/14579335}, author = {Jeffrey Skolnick and Zhang, Yang and Arakaki, Adrian K and Andrzej Koli{\'n}ski and Michal Boniecki and Szil{\'a}gyi, Andr{\'a}s and Daisuke Kihara} } @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 {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 {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 {Kolinski1999, title = {Dynamics and thermodynamics of beta-hairpin assembly: insights from various simulation techniques}, journal = {Biophysical Journal}, volume = {77}, number = {6}, year = {1999}, month = {dec}, pages = {2942{\textendash}52}, abstract = {Small peptides that might have some features of globular proteins can provide important insights into the protein folding problem. Two simulation methods, Monte Carlo Dynamics (MCD), based on the Metropolis sampling scheme, and Entropy Sampling Monte Carlo (ESMC), were applied in a study of a high-resolution lattice model of the C-terminal fragment of the B1 domain of protein G. The results provide a detailed description of folding dynamics and thermodynamics and agree with recent experimental findings (. Nature. 390:196-197). In particular, it was found that the folding is cooperative and has features of an all-or-none transition. Hairpin assembly is usually initiated by turn formation; however, hydrophobic collapse, followed by the system rearrangement, was also observed. The denatured state exhibits a substantial amount of fluctuating helical conformations, despite the strong beta-type secondary structure propensities encoded in the sequence.}, keywords = {Amino Acid Sequence, Animals, Biophysical Phenomena, Biophysics, Models, Molecular, Molecular Sequence Data, Monte Carlo Method, Nerve Tissue Proteins, Nerve Tissue Proteins: chemistry, Protein Conformation, Protein Folding, Protein Structure, Proteins, Proteins: chemistry, Secondary, Thermodynamics}, issn = {0006-3495}, doi = {10.1016/S0006-3495(99)77127-4}, url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1300567\&tool=pmcentrez\&rendertype=abstract}, author = {Andrzej Koli{\'n}ski and Bartosz Ilkowski 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 {Ortiz1998, title = {Fold assembly of small proteins using monte carlo simulations driven by restraints derived from multiple sequence alignments}, journal = {Journal of Molecular Biology}, volume = {277}, number = {2}, year = {1998}, month = {mar}, pages = {419{\textendash}448}, abstract = {The feasibility of predicting the global fold of small proteins by incorporating predicted secondary and tertiary restraints into ab initio folding simulations has been demonstrated on a test set comprised of 20 non-homologous proteins, of which one was a blind prediction of target 42 in the recent CASP2 contest. These proteins contain from 37 to 100 residues and represent all secondary structural classes and a representative variety of global topologies. Secondary structure restraints are provided by the PHD secondary structure prediction algorithm that incorporates multiple sequence information. Predicted tertiary restraints are derived from multiple sequence alignments via a two-step process. First, seed side-chain contacts are identified from correlated mutation analysis, and then a threading-based algorithm is used to expand the number of these seed contacts. A lattice-based reduced protein model and a folding algorithm designed to incorporate these predicted restraints is described. Depending upon fold complexity, it is possible to assemble native-like topologies whose coordinate root-mean-square deviation from native is between 3.0 A and 6.5 A. The requisite level of accuracy in side-chain contact map prediction can be roughly 25\% on average, provided that about 60\% of the contact predictions are correct within +/-1 residue and 95\% of the predictions are correct within +/-4 residues. Precision in tertiary contact prediction is more critical than absolute accuracy. Furthermore, only a subset of the tertiary contacts, on the order of 25\% of the total, is sufficient for successful topology assembly. Overall, this study suggests that the use of restraints derived from multiple sequence alignments combined with a fold assembly algorithm holds considerable promise for the prediction of the global topology of small proteins.}, keywords = {Amino Acid Sequence, Chemical, Models, Molecular Sequence Data, Monte Carlo Method, Protein Folding, Protein Structure, Secondary, Tertiary}, issn = {0022-2836}, doi = {10.1006/jmbi.1997.1595}, url = {http://www.ncbi.nlm.nih.gov/pubmed/9514747}, author = {Angel. R. Ortiz and Andrzej Koli{\'n}ski and Jeffrey Skolnick} } @article {Ortiz1998a, title = {Nativelike topology assembly of small proteins using predicted restraints in Monte Carlo folding simulations}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {95}, number = {3}, year = {1998}, month = {feb}, pages = {1020{\textendash}1025}, abstract = {By incorporating predicted secondary and tertiary restraints derived from multiple sequence alignments into ab initio folding simulations, it has been possible to assemble native-like tertiary structures for a test set of 19 nonhomologous proteins ranging from 29 to 100 residues in length and representing all secondary structural classes. Secondary structural restraints are provided by the PHD secondary structure prediction algorithm that incorporates multiple sequence information. Multiple sequence alignments also provide predicted tertiary restraints via a two-step process: First, seed side chain contacts are selected from a correlated mutation analysis, and then an inverse folding algorithm expands these seed contacts. The predicted secondary and tertiary restraints are incorporated into a lattice-based, reduced protein model for structure assembly and refinement. The resulting native-like topologies exhibit a coordinate root-mean-square deviation from native for the whole chain between 3.1 and 6.7 A, with values ranging from 2.6 to 4.1 A over approximately 80\% of the structure. Overall, this study suggests that the use of restraints derived from multiple sequence alignments combined with a fold assembly algorithm is a promising approach to the prediction of the global topology of small proteins.}, keywords = {Algorithms, Models, Molecular, Monte Carlo Method, Protein Folding, Protein Structure, Secondary, Sequence Alignment, Software, Tertiary}, issn = {0027-8424}, url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=18658\&tool=pmcentrez\&rendertype=abstract}, author = {Angel. R. Ortiz and Andrzej Koli{\'n}ski and Jeffrey Skolnick} } @article {Ortiz1998b, title = {Tertiary structure prediction of the KIX domain of CBP using Monte Carlo simulations driven by restraints derived from multiple sequence alignments}, journal = {Proteins}, volume = {30}, number = {3}, year = {1998}, pages = {287{\textendash}294}, abstract = {Using a recently developed protein folding algorithm, a prediction of the tertiary structure of the KIX domain of the CREB binding protein is described. The method incorporates predicted secondary and tertiary restraints derived from multiple sequence alignments in a reduced protein model whose conformational space is explored by Monte Carlo dynamics. Secondary structure restraints are provided by the PHD secondary structure prediction algorithm that was modified for the presence of predicted U-turns, i.e., regions where the chain reverses global direction. Tertiary restraints are obtained via a two-step process: First, seed side-chain contacts are identified from a correlated mutation analysis, and then, a threading-based algorithm expands the number of these seed contacts. Blind predictions indicate that the KIX domain is a putative three-helix bundle, although the chirality of the bundle could not be uniquely determined. The expected root-mean-square deviation for the correct chirality of the KIX domain is between 5.0 and 6.2 A. This is to be compared with the estimate of 12.9 A that would be expected by a random prediction, using the model of F. Cohen and M. Sternberg (J. Mol. Biol. 138:321-333, 1980).}, keywords = {Algorithms, Amino Acid Sequence, CREB-Binding Protein, Databases as Topic, Models, Molecular, Molecular Sequence Data, Monte Carlo Method, Mutation, Mutation: genetics, Nuclear Proteins, Nuclear Proteins: chemistry, Protein Folding, Protein Structure, Secondary, Sequence Alignment, Tertiary, Trans-Activators, Transcription Factors, Transcription Factors: chemistry}, issn = {0887-3585}, url = {http://www.ncbi.nlm.nih.gov/pubmed/9517544}, author = {Angel. R. Ortiz and Andrzej Koli{\'n}ski and Jeffrey Skolnick} } @article {Hu1997, title = {Improved method for prediction of protein backbone U-turn positions and major secondary structural elements between U-turns}, journal = {Proteins}, volume = {29}, number = {4}, year = {1997}, pages = {443{\textendash}460}, abstract = {A new and more accurate method has been developed for predicting the backbone U-turn positions (where the chain reverses global direction) and the dominant secondary structure elements between U-turns in globular proteins. The current approach uses sequence-specific secondary structure propensities and multiple sequence information. The latter plays an important role in the enhanced success of this approach. Application to two sets (total 108) of small to medium-sized, single-domain proteins indicates that approximately 94\% of the U-turn locations are correctly predicted within three residues, as are 88\% of dominant secondary structure elements. These results are significantly better than our previous method (Kolinski et al., Proteins 27:290-308, 1997). The current study strongly suggests that the U-turn locations are primarily determined by local interactions. Furthermore, both global length constraints and local interactions contribute significantly to the determination of the secondary structure types between U-turns. Accurate U-turn predictions are crucial for accurate secondary structure predictions in the current method. Protein structure modeling, tertiary structure predictions, and possibly, fold recognition should benefit from the predicted structural data provided by this new method.}, keywords = {Amino Acid, Amino Acid Sequence, Amino Acids, Amino Acids: chemistry, Data Interpretation, Models, Molecular, Molecular Sequence Data, Protein Structure, Proteins, Proteins: chemistry, Reproducibility of Results, Secondary, Sequence Alignment, Sequence Alignment: methods, Sequence Alignment: statistics \& numerical data, Sequence Homology, Statistical}, issn = {0887-3585}, url = {http://www.ncbi.nlm.nih.gov/pubmed/9408942}, author = {Wei-Ping Hu and Andrzej Koli{\'n}ski and Jeffrey Skolnick} } @article {Kolinski1997, title = {A method for the prediction of surface "U"-turns and transglobular connections in small proteins}, journal = {Proteins}, volume = {27}, number = {2}, year = {1997}, month = {feb}, pages = {290{\textendash}308}, abstract = {A simple method for predicting the location of surface loops/turns that change the overall direction of the chain that is, "U" turns, and assigning the dominant secondary structure of the intervening transglobular blocks in small, single-domain globular proteins has been developed. Since the emphasis of the method is on the prediction of the major topological elements that comprise the global structure of the protein rather than on a detailed local secondary structure description, this approach is complementary to standard secondary structure prediction schemes. Consequently, it may be useful in the early stages of tertiary structure prediction when establishment of the structural class and possible folding topologies is of interest. Application to a set of small proteins of known structure indicates a high level of accuracy. The prediction of the approximate location of the surface turns/loops that are responsible for the change in overall chain direction is correct in more than 95\% of the cases. The accuracy for the dominant secondary structure assignment for the linear blocks between such surface turns/loops is in the range of 82\%.}, keywords = {Algorithms, Amino Acid Sequence, Animals, Humans, Molecular Sequence Data, Protein Folding, Protein Structure, Proteins, Proteins: chemistry, Secondary}, issn = {0887-3585}, url = {http://www.ncbi.nlm.nih.gov/pubmed/9061792}, author = {Andrzej Koli{\'n}ski and Jeffrey Skolnick and Adam Godzik and Wei-Ping Hu} } @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 {Skolnick1993, title = {From independent modules to molten globules: observations on the nature of protein folding intermediates}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {90}, number = {6}, year = {1993}, pages = {2099{\textendash}100}, keywords = {Binding Sites, Isomerases, Isomerases: chemistry, Protein Disulfide-Isomerases, Protein Folding, Protein Structure, Proteins, Proteins: chemistry, Secondary}, issn = {0027-8424}, url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=46030\&tool=pmcentrez\&rendertype=abstract}, author = {Jeffrey Skolnick and Andrzej Koli{\'n}ski and Adam Godzik} }