@article {388, title = {Identifying knots in proteins.}, journal = {Biochemical Society Transactions}, volume = {41}, year = {2013}, month = {2013 Apr}, pages = {533-7}, abstract = {Polypeptide chains form open knots in many proteins. How these knotted proteins fold and finding the evolutionary advantage provided by these knots are among some of the key questions currently being studied in the protein folding field. The detection and identification of protein knots are substantial challenges. Different methods and many variations of them have been employed, but they can give different results for the same protein. In the present article, we review the various knot identification algorithms and compare their relative strengths when applied to the study of knots in proteins. We show that the statistical approach based on the uniform closure method is advantageous in comparison with other methods used to characterize protein knots.}, keywords = {Animals, Humans, Models, Molecular, Protein Conformation, Proteins}, issn = {1470-8752}, doi = {10.1042/BST20120339}, author = {Millett, Kenneth C and Rawdon, Eric J and Stasiak, Andrzej and Joanna I. Sulkowska} } @article {389, title = {Knot localization in proteins.}, journal = {Biochemical Society Transactions}, volume = {41}, year = {2013}, month = {2013 Apr}, pages = {538-41}, abstract = {The backbones of proteins form linear chains. In the case of some proteins, these chains can be characterized as forming linear open knots. The knot type\ of the full chain reveals only limited information about the entanglement of the chain since, for example, subchains of an unknotted protein can form knots and subchains of a knotted protein can form different types\ of knots than the entire protein. To understand fully the entanglement within the backbone of a given protein, a complete analysis of the knotting within all of the subchains of that protein is necessary. In the present article, we review efforts to characterize the full knotting complexity within individual proteins and present a matrix that conveys information about various aspects of protein knotting. For a given protein, this matrix identifies the precise localization of knotted regions and shows the knot types\ formed by all subchains. The pattern in the matrix can be considered as a knotting fingerprint of that protein. We observe that knotting fingerprints of distantly related knotted proteins are strongly conserved during evolution and discuss how some characteristic motifs in the knotting fingerprints are related to the structure of the knotted regions and their possible biological role.}, keywords = {Animals, Humans, Models, Molecular, Protein Conformation, Proteins}, issn = {1470-8752}, doi = {10.1042/BST20120329}, author = {Rawdon, Eric J and Millett, Kenneth C and Joanna I. Sulkowska and Stasiak, Andrzej} } @article {387, title = {Knotting pathways in proteins.}, journal = {Biochemical Society Transactions}, volume = {41}, year = {2013}, month = {2013 Apr}, pages = {523-7}, abstract = {Most proteins, in order to perform their biological function, have to fold to a compact native state. The increasing number of knotted and slipknotted proteins identified suggests that proteins are able to manoeuvre around topological barriers during folding. In the present article, we review the current progress in elucidating the knotting process in proteins. Although we concentrate on theoretical approaches, where a knotted topology can be unambiguously detected, comparison with experiments is also reviewed. Numerical simulations suggest that the folding process for small knotted proteins is composed of twisted loop formation and then threading by either slipknot geometries or flipping. As the size of the knotted proteins increases, particularly for more deeply threaded termini, the prevalence of traps in the free energy landscape also increases. Thus, in the case of longer knotted and slipknotted proteins, the folding mechanism is probably supported by chaperones. Overall, results imply that knotted proteins can be folded efficiently and survive evolutionary pressure in order to perform their biological functions.}, keywords = {Animals, Humans, Protein Conformation, Protein Engineering, Protein Folding, Proteins, Thermodynamics}, issn = {1470-8752}, doi = {10.1042/BST20120342}, author = {Joanna I. Sulkowska and Noel, Jeffrey K and Ram{\'\i}rez-Sarmiento, C{\'e}sar A and Rawdon, Eric J and Millett, Kenneth C and Onuchic, Jos{\'e} N} } @article {Gniewek2012a, title = {Coarse-grained modeling of mucus barrier properties}, journal = {Biophysical Journal}, volume = {102}, number = {2}, year = {2012}, month = {jan}, pages = {195{\textendash}200}, abstract = {

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

}, keywords = {Adhesives, Adhesives: chemistry, Adhesives: metabolism, Glycocalyx, Glycocalyx: chemistry, Glycocalyx: metabolism, Models, Molecular, Mucins, Mucins: chemistry, Mucins: metabolism, Mucus, Mucus: chemistry, Mucus: cytology, Mucus: metabolism, Nanoparticles, Nanoparticles: chemistry, Protein Conformation, Surface Properties}, issn = {1542-0086}, doi = {10.1016/j.bpj.2011.11.4010}, url = {http://www.ncbi.nlm.nih.gov/pubmed/22339855}, author = {Pawel Gniewek and Andrzej Koli{\'n}ski} } @article {406, title = {Conservation of complex knotting and slipknotting patterns in proteins.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {109}, year = {2012}, month = {2012 Jun 26}, pages = {E1715-23}, abstract = {While analyzing all available protein structures for the presence of knots and slipknots, we detected a strict conservation of complex knotting patterns within and between several protein families despite their large sequence divergence. Because protein folding pathways leading to knotted native protein structures are slower and less efficient than those leading to unknotted proteins with similar size and sequence, the strict conservation of the knotting patterns indicates an important physiological role of knots and slipknots in these proteins. Although little is known about the functional role of knots, recent studies have demonstrated a protein-stabilizing ability of knots and slipknots. Some of the conserved knotting patterns occur in proteins forming transmembrane channels where the slipknot loop seems to strap together the transmembrane helices forming the channel.}, keywords = {Protein Conformation, Protein Folding, Proteins}, issn = {1091-6490}, doi = {10.1073/pnas.1205918109}, author = {Joanna I. Sulkowska and Rawdon, Eric J and Millett, Kenneth C and Onuchic, Jos{\'e} N and Stasiak, Andrzej} } @article {Latek2011, title = {CABS-NMR{\textendash}De novo tool for rapid global fold determination from chemical shifts, residual dipolar couplings and sparse methyl-methyl NOEs}, journal = {Journal of c\Computational Chemistry}, volume = {32}, number = {3}, year = {2011}, pages = {536{\textendash}44}, abstract = {Recent development of nuclear magnetic resonance (NMR) techniques provided new types of structural restraints that can be successfully used in fast and low-cost global protein fold determination. Here, we present CABS-NMR, an efficient protein modeling tool, which takes advantage of such structural restraints. The restraints are converted from original NMR data to fit the coarse grained protein representation of the C-Alpha-Beta-Side-group (CABS) algorithm. CABS is a Monte Carlo search algorithm that uses a knowledge-based force field. Its versatile structure enables a variety of protein-modeling protocols, including purely de novo folding, folding guided by restraints derived from template structures or, structure assembly based on experimental data. In particular, CABS-NMR uses the distance and angular restraints set derived from various NMR experiments. This new modeling technique was successfully tested in structure determination of 10 globular proteins of size up to 216 residues, for which sparse NMR data were available. Additional detailed analysis was performed for a S100A1 protein. Namely, we successfully predicted Nuclear Overhauser Effect signals on the basis of low-energy structures obtained from chemical shifts by CABS-NMR. It has been observed that utility of chemical shifts and other types of experimental data (i.e. residual dipolar couplings and methyl-methyl Nuclear Overhauser Effect signals) in the presented modeling pipeline depends mainly on size of a protein and complexity of its topology. In this work, we have provided tools for either post-experiment processing of various kinds of NMR data or fast and low-cost structural analysis in the still challenging field of new fold predictions.}, keywords = {Algorithms, Animals, Cattle, Magnetic Resonance Spectroscopy, Magnetic Resonance Spectroscopy: methods, Models, Molecular, Monte Carlo Method, Protein Conformation, Protein Folding, Proteins, Proteins: chemistry, S100 Proteins, S100 Proteins: chemistry}, issn = {1096-987X}, doi = {10.1002/jcc.21640}, url = {http://www.ncbi.nlm.nih.gov/pubmed/20806263}, author = {Dorota Latek and Andrzej Koli{\'n}ski} } @article {Gniewek2011a, title = {Multibody coarse-grained potentials for native structure recognition and quality assessment of protein models}, journal = {Proteins}, volume = {79}, number = {6}, year = {2011}, month = {jun}, pages = {1923{\textendash}9}, abstract = {Multibody potentials have been of much interest recently because they take into account three dimensional interactions related to residue packing and capture the cooperativity of these interactions in protein structures. Our goal was to combine long range multibody potentials and short range potentials to improve recognition of native structure among misfolded decoys. We optimized the weights for four-body nonsequential, four-body sequential, and short range potentials to obtain optimal model ranking results for threading and have compared these data against results obtained with other potentials (26 different coarse-grained potentials from the Potentials {\textquoteright}R{\textquoteright}Us web server have been used). Our optimized multibody potentials outperform all other contact potentials in the recognition of the native structure among decoys, both for models from homology template-based modeling and from template-free modeling in CASP8 decoy sets. We have compared the results obtained for this optimized coarse-grained potentials, where each residue is represented by a single point, with results obtained by using the DFIRE potential, which takes into account atomic level information of proteins. We found that for all proteins larger than 80 amino acids our optimized coarse-grained potentials yield results comparable to those obtained with the atomic DFIRE potential.}, keywords = {Amino Acids, Amino Acids: chemistry, Computational Biology, Computational Biology: methods, Models, Molecular, Protein Conformation, Proteins, Proteins: chemistry}, issn = {1097-0134}, doi = {10.1002/prot.23015}, url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3093657\&tool=pmcentrez\&rendertype=abstract}, author = {Pawel Gniewek and Sumudu P. Leelananda and Andrzej Koli{\'n}ski and Robert L. Jernigan and Andrzej Kloczkowski} } @article {Kmiecik2011, title = {Simulation of chaperonin effect on protein folding: a shift from nucleation-condensation to framework mechanism}, journal = {Journal of the American Chemical Society}, volume = {133}, number = {26}, year = {2011}, month = {jul}, pages = {10283{\textendash}9}, abstract = {

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

}, keywords = {Chaperonins, Chaperonins: metabolism, Computational Biology, Models, Molecular, Protein Conformation, protein dynamics, Protein Folding, Protein Structure, Staphylococcal Protein A, Staphylococcal Protein A: chemistry, Staphylococcal Protein A: metabolism, Stochastic Processes, Tertiary}, issn = {1520-5126}, doi = {10.1021/ja203275f}, url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3132998\&tool=pmcentrez\&rendertype=abstract}, author = {Sebastian Kmiecik and Andrzej Koli{\'n}ski} } @article {409, title = {Slipknotting upon native-like loop formation in a trefoil knot protein.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {107}, year = {2010}, month = {2010 Aug 31}, pages = {15403-8}, abstract = {Protein knots and slipknots, mostly regarded as intriguing oddities, are gradually being recognized as significant structural motifs. Recent experimental results show that knotting, starting from a fully extended polypeptide, has not yet been observed. Understanding the nucleation process of folding knots is thus a natural challenge for both experimental and theoretical investigation. In this study, we employ energy landscape theory and molecular dynamics to elucidate the entire folding mechanism. The full free energy landscape of a knotted protein is mapped using an all-atom structure-based protein model. Results show that, due to the topological constraint, the protein folds through a three-state mechanism that contains (i) a precise nucleation site that creates a correctly twisted native loop (first barrier) and (ii) a rate-limiting free energy barrier that is traversed by two parallel knot-forming routes. The main route corresponds to a slipknot conformation, a collapsed configuration where the C-terminal helix adopts a hairpin-like configuration while threading, and the minor route to an entropically limited plug motion, where the extended terminus is threaded as through a needle. Knot formation is a late transition state process and results show that random (nonspecific) knots are a very rare and unstable set of configurations both at and below folding temperature. Our study shows that a native-biased landscape is sufficient to fold complex topologies and presents a folding mechanism generalizable to all known knotted protein topologies: knotting via threading a native-like loop in a preordered intermediate.}, keywords = {Algorithms, Archaea, Archaeal Proteins, Crystallization, Databases, Protein, Models, Molecular, Molecular Dynamics Simulation, Protein Conformation, Protein Folding, Protein Multimerization, Protein Structure, Secondary, Protein Structure, Tertiary, Thermodynamics}, issn = {1091-6490}, doi = {10.1073/pnas.1009522107}, author = {Noel, Jeffrey K and Joanna I. Sulkowska and Onuchic, Jos{\'e} N} } @article {410, title = {A Stevedore{\textquoteright}s protein knot.}, journal = {PLoS Comput Biol}, volume = {6}, year = {2010}, month = {2010 Apr}, pages = {e1000731}, abstract = {Protein knots, mostly regarded as intriguing oddities, are gradually being recognized as significant structural motifs. Seven distinctly knotted folds have already been identified. It is by and large unclear how these exceptional structures actually fold, and only recently, experiments and simulations have begun to shed some light on this issue. In checking the new protein structures submitted to the Protein Data Bank, we encountered the most complex and the smallest knots to date: A recently uncovered alpha-haloacid dehalogenase structure contains a knot with six crossings, a so-called Stevedore knot, in a projection onto a plane. The smallest protein knot is present in an as yet unclassified protein fragment that consists of only 92 amino acids. The topological complexity of the Stevedore knot presents a puzzle as to how it could possibly fold. To unravel this enigma, we performed folding simulations with a structure-based coarse-grained model and uncovered a possible mechanism by which the knot forms in a single loop flip.}, keywords = {Databases, Protein, Hydrolases, Molecular Dynamics Simulation, Protein Conformation, Protein Folding}, issn = {1553-7358}, doi = {10.1371/journal.pcbi.1000731}, author = {B{\"o}linger, Daniel and Joanna I. Sulkowska and Hsu, Hsiao-Ping and Mirny, Leonid A and Kardar, Mehran and Onuchic, Jos{\'e} N and Virnau, Peter} } @article {Trojanowski2010, title = {TRACER. A new approach to comparative modeling that combines threading with free-space conformational sampling}, journal = {Acta Biochimica Polonica}, volume = {57}, number = {1}, year = {2010}, month = {jan}, pages = {125{\textendash}33}, abstract = {A new approach to comparative modeling of proteins, TRACER, is described and benchmarked against classical modeling procedures. The new method unifies true three-dimensional threading with coarse-grained sampling of query protein conformational space. The initial sequence alignment of a query protein with a template is not required, although a template needs to be somehow identified. The template is used as a multi-featured fuzzy three-dimensional scaffold. The conformational search for the query protein is guided by intrinsic force field of the coarse-grained modeling engine CABS and by compatibility with the template scaffold. During Replica Exchange Monte Carlo simulations the model chain representing the query protein finds the best possible structural alignment with the template chain, that also optimizes the intra-protein interactions as approximated by the knowledge based force field of CABS. The benchmark done for a representative set of query/template pairs of various degrees of sequence similarity showed that the new method allows meaningful comparative modeling also for the region of marginal, or non-existing, sequence similarity. Thus, the new approach significantly extends the applicability of comparative modeling.}, keywords = {Computational Biology, Computational Biology: methods, Imaging, Models, Molecular, Protein Conformation, Proteins, Proteins: chemistry, Three-Dimensional, Three-Dimensional: methods}, issn = {1734-154X}, url = {http://www.ncbi.nlm.nih.gov/pubmed/20309433}, author = {Sebastian Trojanowski and Aleksandra Rutkowska and Andrzej Koli{\'n}ski} } @article {408, title = {Untying knots in proteins.}, journal = {Journal of the American Chemical Society}, volume = {132}, year = {2010}, month = {2010 Oct 13}, pages = {13954-6}, abstract = {A shoelace can be readily untied by pulling its ends rather than its loops. Attempting to untie a native knot in a protein can also succeed or fail depending on where one pulls. However, thermal fluctuations induced by the surrounding water affect conformations stochastically and may add to the uncertainty of the outcome. When the protein is pulled by the termini, the knot can only get tightened, and any attempt at untying results in failure. We show that, by pulling specific amino acids, one may easily retract a terminal segment of the backbone from the knotting loop and untangle the knot. At still other amino acids, the outcome of pulling can go either way. We study the dependence of the untying probability on the way the protein is grasped, the pulling speed, and the temperature. Elucidation of the mechanisms underlying this dependence is critical for a successful experimental realization of protein knot untying.}, keywords = {Amino Acids, Protein Conformation, Proteins}, issn = {1520-5126}, doi = {10.1021/ja102441z}, author = {Joanna I. Sulkowska and Su{\l}kowski, Piotr and Szymczak, Piotr and Cieplak, Marek} } @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 {411, title = {Jamming proteins with slipknots and their free energy landscape.}, journal = {Phys Rev Lett}, volume = {103}, year = {2009}, month = {2009 Dec 31}, pages = {268103}, abstract = {Theoretical studies of stretching proteins with slipknots reveal a surprising growth of their unfolding times when the stretching force crosses an intermediate threshold. This behavior arises as a consequence of the existence of alternative unfolding routes that are dominant at different force ranges. The existence of an intermediate, metastable configuration where the slipknot is jammed is responsible for longer unfolding times at higher forces. Simulations are performed with a coarse-grained model with further quantification using a refined description of the geometry of the slipknots. The simulation data are used to determine the free energy landscape of the protein, which supports recent analytical predictions.}, keywords = {Protein Conformation, Protein Folding, Proteins, Thermodynamics, Time Factors}, issn = {1079-7114}, author = {Joanna I. Sulkowska and Su{\l}kowski, Piotr and Onuchic, Jos{\'e} N} } @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 {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 {416, title = {Selection of optimal variants of Go-like models of proteins through studies of stretching.}, journal = {Biophys J}, volume = {95}, year = {2008}, month = {2008 Oct}, pages = {3174-91}, abstract = {The Go-like models of proteins are constructed based on the knowledge of the native conformation. However, there are many possible choices of a Hamiltonian for which the ground state coincides with the native state. Here, we propose to use experimental data on protein stretching to determine what choices are most adequate physically. This criterion is motivated by the fact that stretching processes usually start with the native structure, in the vicinity of which the Go-like models should work the best. Our selection procedure is applied to 62 different versions of the Go model and is based on 28 proteins. We consider different potentials, contact maps, local stiffness energies, and energy scales--uniform and nonuniform. In the latter case, the strength of the nonuniformity was governed either by specificity or by properties related to positioning of the side groups. Among them is the simplest variant: uniform couplings with no i, i + 2 contacts. This choice also leads to good folding properties in most cases. We elucidate relationship between the local stiffness described by a potential which involves local chirality and the one which involves dihedral and bond angles. The latter stiffness improves folding but there is little difference between them when it comes to stretching.}, keywords = {Analysis of Variance, Biomechanical Phenomena, Models, Molecular, Protein Conformation, Protein Folding, Proteins, Reproducibility of Results, Temperature, Thermodynamics}, issn = {1542-0086}, doi = {10.1529/biophysj.107.127233}, author = {Joanna I. Sulkowska and Cieplak, Marek} } @article {417, title = {Tightening of knots in proteins.}, journal = {Phys Rev Lett}, volume = {100}, year = {2008}, month = {2008 Feb 8}, pages = {058106}, abstract = {We perform theoretical studies of stretching of 20 proteins with knots within a coarse-grained model. The knot{\textquoteright}s ends are found to jump to well defined sequential locations that are associated with sharp turns, whereas in homopolymers they diffuse around and eventually slide off. The waiting times of the jumps are increasingly stochastic as the temperature is raised. Knots typically do not return to their native locations when a protein is released after stretching.}, keywords = {Algorithms, Diffusion, Models, Molecular, Protein Conformation, Solvents, Stochastic Processes, Temperature}, issn = {0031-9007}, author = {Joanna I. Sulkowska and Su{\l}kowski, Piotr and Szymczak, P and Cieplak, Marek} } @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 {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 {Ibryashkina2007, title = {Type II restriction endonuclease R.Eco29kI is a member of the GIY-YIG nuclease superfamily}, journal = {BMC Structural Biology}, volume = {7}, year = {2007}, month = {jan}, pages = {48}, abstract = {BACKGROUND: The majority of experimentally determined crystal structures of Type II restriction endonucleases (REases) exhibit a common PD-(D/E)XK fold. Crystal structures have been also determined for single representatives of two other folds: PLD (R.BfiI) and half-pipe (R.PabI), and bioinformatics analyses supported by mutagenesis suggested that some REases belong to the HNH fold. Our previous bioinformatic analysis suggested that REase R.Eco29kI shares sequence similarities with one more unrelated nuclease superfamily, GIY-YIG, however so far no experimental data were available to support this prediction. The determination of a crystal structure of the GIY-YIG domain of homing endonuclease I-TevI provided a template for modeling of R.Eco29kI and prompted us to validate the model experimentally. RESULTS: Using protein fold-recognition methods we generated a new alignment between R.Eco29kI and I-TevI, which suggested a reassignment of one of the putative catalytic residues. A theoretical model of R.Eco29kI was constructed to illustrate its predicted three-dimensional fold and organization of the active site, comprising amino acid residues Y49, Y76, R104, H108, E142, and N154. A series of mutants was constructed to generate amino acid substitutions of selected residues (Y49A, R104A, H108F, E142A and N154L) and the mutant proteins were examined for their ability to bind the DNA containing the Eco29kI site 5{\textquoteright}-CCGCGG-3{\textquoteright} and to catalyze the cleavage reaction. Experimental data reveal that residues Y49, R104, E142, H108, and N154 are important for the nuclease activity of R.Eco29kI, while H108 and N154 are also important for specific DNA binding by this enzyme. CONCLUSION: Substitutions of residues Y49, R104, H108, E142 and N154 predicted by the model to be a part of the active site lead to mutant proteins with strong defects in the REase activity. These results are in very good agreement with the structural model presented in this work and with our prediction that R.Eco29kI belongs to the GIY-YIG superfamily of nucleases. Our study provides the first experimental evidence for a Type IIP REase that does not belong to the PD-(D/E)XK or HNH superfamilies of nucleases, and is instead a member of the unrelated GIY-YIG superfamily.}, keywords = {Amino Acid Sequence, Binding Sites, Computational Biology, Computational Biology: methods, Deoxyribonucleases, DNA, DNA Cleavage, DNA: metabolism, Electrophoretic Mobility Shift Assay, Models, Molecular, Molecular Sequence Data, Mutation, Protein, Protein Conformation, Sequence Alignment, Structural Homology, Type II Site-Specific, Type II Site-Specific: chemist, Type II Site-Specific: metabol}, isbn = {1472680774}, issn = {1472-6807}, doi = {10.1186/1472-6807-7-48}, url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1952068\&tool=pmcentrez\&rendertype=abstract}, author = {Elena M. Ibryashkina and Marina V. Zakharova and Vladimir B. Baskunov and Ekaterina S. Bogdanova and Maxim O. Nagornykh and Marat M Den{\textquoteright}mukhamedov and Bogdan S. Melnik and Andrzej Koli{\'n}ski and Dominik Gront and Marcin Feder and Alexander S. Solonin and Janusz M. Bujnicki} } @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 {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 {Kolinski2004, title = {Protein modeling and structure prediction with a reduced representation}, journal = {Acta Biochimica Polonica}, volume = {51}, number = {2}, year = {2004}, month = {jan}, pages = {349{\textendash}71}, abstract = {

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

}, keywords = {Amino Acid Sequence, Animals, Carbon, Carbon: chemistry, Crystallography, Databases as Topic, Humans, Hydrogen Bonding, Mathematics, Models, Molecular, Molecular Sequence Data, Protein Conformation, Protein Structure, Proteins, Proteins: chemistry, Proteomics, Proteomics: methods, Tertiary, Theoretical, X-Ray}, issn = {0001-527X}, doi = {035001349}, url = {http://www.ncbi.nlm.nih.gov/pubmed/15218533}, author = {Andrzej Koli{\'n}ski} } @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 {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 {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 {291, title = {TOUCHSTONEX: protein structure prediction with sparse NMR data}, journal = {Proteins}, volume = {53}, year = {2003}, month = {2003 Nov 1}, pages = {290-306}, abstract = {TOUCHSTONEX, a new method for folding proteins that uses a small number of long-range contact restraints derived from NMR experimental NOE (nuclear Overhauser enhancement) data, is described. The method employs a new lattice-based, reduced model of proteins that explicitly represents C(alpha), C(beta), and the sidechain centers of mass. The force field consists of knowledge-based terms to produce protein-like behavior, including various short-range interactions, hydrogen bonding, and one-body, pairwise, and multibody long-range interactions. Contact restraints were incorporated into the force field as an NOE-specific pairwise potential. We evaluated the algorithm using a set of 125 proteins of various secondary structure types and lengths up to 174 residues. Using N/8 simulated, long-range sidechain contact restraints, where N is the number of residues, 108 proteins were folded to a C(alpha)-root-mean-square deviation (RMSD) from native below 6.5 A. The average RMSD of the lowest RMSD structures for all 125 proteins (folded and unfolded) was 4.4 A. The algorithm was also applied to limited experimental NOE data generated for three proteins. Using very few experimental sidechain contact restraints, and a small number of sidechain-main chain and main chain-main chain contact restraints, we folded all three proteins to low-to-medium resolution structures. The algorithm can be applied to the NMR structure determination process or other experimental methods that can provide tertiary restraint information, especially in the early stage of structure determination, when only limited data are available.}, keywords = {Algorithms, Amino Acids, Models, Molecular, Nuclear Magnetic Resonance, Biomolecular, Protein Conformation, Protein Folding, Protein Structure, Tertiary, Proteins, Staphylococcal Protein A}, issn = {1097-0134}, doi = {10.1002/prot.10499}, author = {Wei Li and Yang Zhang and Daisuke Kihara and Yuanpeng Janet Huang and Deyou Zheng and Gaetano T. Montelione 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 {Rotkiewicz2001, title = {Model of three-dimensional structure of vitamin D receptor and its binding mechanism with 1alpha,25-dihydroxyvitamin D(3)}, journal = {Proteins}, volume = {44}, number = {3}, year = {2001}, month = {2001}, pages = {188{\textendash}199}, abstract = {Comparative modeling of the vitamin D receptor three-dimensional structure and computational docking of 1alpha,25-dihydroxyvitamin D(3) into the putative binding pocket of the two deletion mutant receptors: (207-423) and (120-422, Delta [164-207]) are reported and evaluated in the context of extensive mutagenic analysis and crystal structure of holo hVDR deletion protein published recently. The obtained molecular model agrees well with the experimentally determined structure. Six different conformers of 1alpha,25-dihydroxyvitamin D(3) were used to study flexible docking to the receptor. On the basis of values of conformational energy of various complexes and their consistency with functional activity, it appears that 1alpha,25-dihydroxyvitamin D(3) binds the receptor in its 6-s-trans form. The two lowest energy complexes obtained from docking the hormone into the deletion protein (207-423) differ in conformation of ring A and orientation of the ligand molecule in the VDR pocket. 1alpha,25-Dihydroxyvitamin D(3) possessing the A-ring conformation with axially oriented 1alpha-hydroxy group binds receptor with its 25-hydroxy substituent oriented toward the center of the receptor cavity, whereas ligand possessing equatorial conformation of 1alpha-hydroxy enters the pocket with A ring directed inward. The latter conformation and orientation of the ligand is consistent with the crystal structure of hVDR deletion mutant (118-425, Delta [165-215]). The lattice model of rVDR (120-422, Delta [164-207]) shows excellent agreement with the crystal structure of the hVDR mutant. The complex obtained from docking the hormone into the receptor has lower energy than complexes for which homology modeling was used. Thus, a simple model of vitamin D receptor with the first two helices deleted can be potentially useful for designing a general structure of ligand, whereas the advanced lattice model is suitable for examining binding sites in the pocket.}, keywords = {Amino Acid, Amino Acid Sequence, Animals, Binding Sites, Calcitriol, Calcitriol: chemistry, Calcitriol: genetics, Computational Biology, Humans, Ligands, Models, Molecular, Molecular Sequence Data, Point Mutation, Protein Conformation, Protein Structure, Rats, Receptors, Sequence Homology, Tertiary}, issn = {0887-3585}, url = {http://www.ncbi.nlm.nih.gov/pubmed/11455592}, author = {Piotr Rotkiewicz and Wanda Sicinska and Andrzej Koli{\'n}ski and Hector F. DeLuca} } @article {289, title = {Monte Carlo simulation of designed helical proteins}, journal = {Acta Poloniae Pharmaceutica {\textendash} Drug Research}, volume = {57 Suppl}, year = {2000}, month = {2000 Nov}, pages = {119-21}, keywords = {Monte Carlo Method, Protein Conformation, Protein Folding, Protein Structure, Secondary}, issn = {0001-6837}, 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 {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 {Godzik1995, title = {Are proteins ideal mixtures of amino acids? Analysis of energy parameter sets}, journal = {Protein Science: a Publication of the Protein Society}, volume = {4}, number = {10}, year = {1995}, month = {oct}, pages = {2107{\textendash}2117}, abstract = {Various existing derivations of the effective potentials of mean force for the two-body interactions between amino acid side chains in proteins are reviewed and compared to each other. The differences between different parameter sets can be traced to the reference state used to define the zero of energy. Depending on the reference state, the transfer free energy or other pseudo-one-body contributions can be present to various extents in two-body parameter sets. It is, however, possible to compare various derivations directly by concentrating on the "excess" energy-a term that describes the difference between a real protein and an ideal solution of amino acids. Furthermore, the number of protein structures available for analysis allows one to check the consistency of the derivation and the errors by comparing parameters derived from various subsets of the whole database. It is shown that pair interaction preferences are very consistent throughout the database. Independently derived parameter sets have correlation coefficients on the order of 0.8, with the mean difference between equivalent entries of 0.1 kT. Also, the low-quality (low resolution, little or no refinement) structures show similar regularities. There are, however, large differences between interaction parameters derived on the basis of crystallographic structures and structures obtained by the NMR refinement. The origin of the latter difference is not yet understood.}, keywords = {Amino Acid Sequence, Amino Acids, Crystallography, Databases, Factual, Magnetic Resonance Spectroscopy, Mathematics, Models, Protein Conformation, Protein Folding, Proteins, Proteins: chemistry, Theoretical, Thermodynamics, X-Ray}, issn = {0961-8368}, doi = {10.1002/pro.5560041016}, url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2142984\&tool=pmcentrez\&rendertype=abstract}, author = {Adam Godzik and Andrzej Koli{\'n}ski 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 {Skolnick1989, title = {Monte Carlo studies on equilibrium globular protein folding. II. Beta-barrel globular protein models}, journal = {Biopolymers}, volume = {28}, number = {6}, year = {1989}, month = {jun}, pages = {1059{\textendash}95}, abstract = {In the context of dynamic Monte Carlo simulations on a model protein confined to a tetrahedral lattice, the interplay of protein size and tertiary structure, and the requirements for an all-or-none transition to a unique native state, are investigated. Small model proteins having a primary sequence consisting of a central bend neutral region flanked by two tails having an alternating hydrophobic/hydrophilic pattern of residues are seen to undergo a continuous transition to a beta-hairpin collapsed state. On increasing the length of the tails, the beta-hairpin structural motif is found to be in equilibrium with a four-member beta-barrel. Further increase of the tail length results in the shift of the structural equilibrium to the four-member beta-barrel. The random coil to beta-barrel transition is of an all-or-none character, but while the central turn is always the desired native bend, the location of the turns involving the two external strands is variable. That is, beta-barrels having the external stands that are two residues out of register are also observed in the transition region. Introduction into the primary sequence of two additional regions that are at the very least neutral toward turn formation produces an all-or-none transition to the unique, native, four-member beta-barrel. Various factors that can augment the stability of the native conformation are explored. Overall, these folding simulations strongly indicate that the general rules of globular protein folding are rather robust{\textendash}namely, one requires a general pattern of hydrophobic/hydrophilic residues that allow the protein to have a well-defined interior and exterior and the presence of regions in the amino acid sequence that at the very least are locally indifferent to turn formation. Since no site-specific interactions between hydrophobic and hydrophilic residues are required to produce a unique four-member beta-barrel, these simulations strongly suggest that site specificity is involved in structural fine-tuning.}, keywords = {Algorithms, Models, Monte Carlo Method, Protein Conformation, Proteins, Theoretical}, issn = {0006-3525}, doi = {10.1002/bip.360280604}, url = {http://www.ncbi.nlm.nih.gov/pubmed/2730942}, author = {Jeffrey Skolnick and Andrzej Koli{\'n}ski and Robert Yaris} } @article {Kolinski1987, title = {Monte Carlo studies on equilibrium globular protein folding. I. Homopolymeric lattice models of beta-barrel proteins}, journal = {Biopolymers}, volume = {26}, number = {6}, year = {1987}, month = {jun}, pages = {937{\textendash}62}, abstract = {Dynamic Monte Carlo studies have been performed on various diamond lattice models of β-proteins. Unlike previous work, no bias toward the native state is introduced; instead, the protein is allowed to freely hunt through all of phase space to find the equilibrium conformation. Thus, these systems may aid in the elucidation of the rules governing protein folding from a given primary sequence; in particular, the interplay of short- vs long-range interaction can be explored. Three distinct models (A[BOND]C) were examined. In model A, in addition to the preference for trans (t) over gauche states (g+ and g-) (thereby perhaps favoring β-sheet formation), attractive interactions are allowed between all nonbonded, nearest neighbor pairs of segments. If the molecules possess a relatively large fraction of t states in the denatured form, on cooling spontaneous collapse to a well-defined β-barrel is observed. Unfortunately, in model A the denatured state exhibits too much secondary structure to correctly model the globular protein collapse transition. Thus in models B and C, the local stiffness is reduced. In model B, in the absence of long-range interactions, t and g states are equally weighted, and cooperativity is introduced by favoring formation of adjacent pairs of nonbonded (but not necessarily parallel) t states. While the denatured state of these systems behaves like a random coil, their native globular structure is poorly defined. Model C retains the cooperativity of model B but allows for a slight preference of t over g states in the short-range interactions. Here, the denatured state is indistinguishable from a random coil, and the globular state is a well-defined β-barrel. Over a range of chain lengths, the collapse is well represented by an all-or-none model. Hence, model C possesses the essential qualitative features observed in real globular proteins. These studies strongly suggest that the uniqueness of the globular conformation requires some residual secondary structure to be present in the denatured state.}, keywords = {Biological, Models, Monte Carlo Method, Protein Conformation, Proteins}, issn = {0006-3525}, doi = {10.1002/bip.360260613}, url = {http://www.ncbi.nlm.nih.gov/pubmed/3607251}, author = {Andrzej Koli{\'n}ski and Jeffrey Skolnick and Robert Yaris} } @article {Kolinski1986a, title = {Monte Carlo simulations on an equilibrium globular protein folding model}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {83}, number = {19}, year = {1986}, month = {oct}, pages = {7267{\textendash}71}, abstract = {

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

}, keywords = {Models, Protein Conformation, Statistics as Topic, Structural, Structure-Activity Relationship, Temperature, Thermodynamics}, issn = {0027-8424}, url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=386697\&tool=pmcentrez\&rendertype=abstract}, author = {Andrzej Koli{\'n}ski and Jeffrey Skolnick and Robert Yaris} }