Modification and Optimization of the United-Residue (UNRES) Potential Energy Function for Canonical Simulations. I. Temperature Dependence of the Effective Energy Function and Tests of the Optimization Method with Single Training Proteins

Liwo, Adam; Khalili, Mey; Czaplewski, Cezary; Kalinowski, Sebastian; Ołdziej, Stanisław; Wachucik, Katarzyna; Scheraga, Harold A.

doi:10.1021/jp065380a

Cited by 191 publications

(519 citation statements)

References 88 publications

(400 reference statements)

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“…In the first step, MREMD (20,31) simulations were carried out with the use of our coarse-grained UNRES force field (27)(28)(29)(30), with which a molecular dynamics method (26,45) and its multiplexed replica exchange extension (33) were implemented earlier. In the second step, the conformational ensembles obtained by coarse-grained MREMD simulations were analyzed by means of WHAM (34) to determine the heat-capacity profiles and conformational ensembles at any desired temperature, following the procedure described in our earlier work (28). For each system, the heat-capacity profile was analyzed and a temperature of T ≈ T m − 10 K was selected to analyze conformational ensembles, where T m is the temperature of the main heatcapacity peak (the "melting temperature").…”

Section: Methodsmentioning

confidence: 99%

“…For each protein, the rmsd cutoff was selected as a compromise between a small number of families (ideally five, which is the number of models that could be submitted for each target) and grouping similar conformations in a given family. The clusters are ranked according to decreasing probabilities, which are computed from the probabilities of their component conformations calculated by WHAM (28). For each cluster, the conformation closest to the average over the cluster is considered a representative of the whole cluster.…”

Section: Methodsmentioning

confidence: 99%

“…However, coarsegrained approaches (23)(24)(25), in which several atoms are merged into single interaction sites, are used very extensively, because they enable us to treat protein systems at time and dimensional scales, which are orders of magnitude larger (26) than those possible in all-atom computations. During the past 20 y, we have been developing (27)(28)(29)(30) a simplified model for proteins termed UNRES, in which two interaction sites per residue are defined, namely, a united side chain and a united peptide group. The effective energy function has been defined as the potential of mean force of polypeptide chains in water.…”

Section: Significancementioning

confidence: 99%

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Lessons from application of the UNRES force field to predictions of structures of CASP10 targets

Mozolewska

Krupa

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The performance of the physics-based protocol, whose main component is the United Residue (UNRES) physics-based coarse-grained force field, developed in our laboratory for the prediction of protein structure from amino acid sequence, is illustrated. Candidate models are selected, based on probabilities of the conformational families determined by multiplexed replica-exchange simulations, from the 10th Community Wide Experiment on the Critical Assessment of Techniques for Protein Structure Prediction (CASP10). For target T0663, classified as a new fold, which consists of two α + β domains homologous to those of known proteins, UNRES predicted the correct symmetry of packing, in which the domains are rotated with respect to each other by 180°in the experimental structure. By contrast, models obtained by knowledge-based methods, in which each domain is modeled very accurately but not rotated, resulted in incorrect packing. Two UNRES models of this target were featured by the assessors. Correct domain packing was also predicted by UNRES for the homologous target T0644, which has a similar structure to that of T0663, except that the two domains are not rotated. Predictions for two other targets, T0668 and T0684_D2, are among the best ones by global distance test score. These results suggest that our physicsbased method has substantial predictive power. In particular, it has the ability to predict domain-domain orientations, which is a significant advance in the state of the art.protein folding | structure symmetry | multi-domain packing P rediction of protein structures from amino acid sequence still remains an unsolved problem of computational biology. Although, since the famous experiments by Anfinsen (1), it is known that a protein adopts the structure which is the (kinetically reachable) global minimum of the free energy of a system, it is not straightforward to implement this physical principle in practice because of the inaccuracy of existing force fields and because of the enormous difficulty to search the conformational space of the system. Therefore, the most effective methods for protein-structure prediction nowadays are knowledge-based approaches, in which database information is incorporated explicitly into the procedure (2). These methods can be divided into three categories, namely, comparative (homology) modeling (3-5), in which the target sequence is compared with the sequences for which experimental structures are known and those structures are usually selected as candidate models for which the greatest similarity is observed; threading (6-8), in which the target sequence is superposed on structures from a database, and those which give the highest score (lowest pseudoenergy) are selected as candidate predictions; and, finally, the fragment-assembly or minithreading method developed by David Baker and colleagues (9, 10), in which the predicted structure is assembled from nine-residue fragments extracted from a protein-structure database, and knowledge-and physicsbased filters are applied at each asse...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Significancementioning

confidence: 99%

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Lessons from application of the UNRES force field to predictions of structures of CASP10 targets

Mozolewska

Krupa

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…To overcome this problem, many approximate coarse-grained methods have been developed during the past decade (2)(3)(4)(5). One of them makes use of a physics-based united-residue (UNRES) force field developed in our group over the past years (6)(7)(8)(9)(10)(11)(12)(13)(14) (SI Appendix, Fig. S1 and SI Materials and Methods).…”

mentioning

confidence: 99%

Folding kinetics of WW domains with the united residue force field for bridging microscopic motions and experimental measurements

Zhou

Maisuradze

Suñol

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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To demonstrate the utility of the coarse-grained united-residue (UNRES) force field to compare experimental and computed kinetic data for folding proteins, we have performed long-time millisecondtimescale canonical Langevin molecular dynamics simulations of the triple β-strand from the Formin binding protein 28 WW domain and six nonnatural variants, using UNRES. The results have been compared with available experimental data in both a qualitative and a quantitative manner. Complexities of the folding pathways, which cannot be determined experimentally, were revealed. The folding mechanisms obtained from the simulated folding kinetics are in agreement with experimental results, with a few discrepancies for which we have accounted. The origins of single-and double-exponential kinetics and their correlations with two-and three-state folding scenarios are shown to be related to the relative barrier heights between the various states. The rate constants obtained from time profiles of the fractions of the native, intermediate, and unfolded structures, and the kinetic equations fitted to them, correlate with the experimental values; however, they are about three orders of magnitude larger than the experimental ones for most of the systems. These differences are in agreement with the timescale extension derived by scaling down the friction of water and averaging out the fast degrees of freedom when passing from all-atom to a coarse-grained representation. Our results indicate that the UNRES force field can provide accurate predictions of folding kinetics of these WW domains, often used as models for the study of the mechanisms of proein folding.FBP28 WW domain | nonnatural variants | folding rates | free-energy landscapes | millisecond-timescale canonical MD simulations R ecent advances in computer simulation techniques have facilitated the direct study of the folding process of small fastfolding proteins, using all-atom force fields (1). However, it is important to validate the simulation methodologies, and the only way to accomplish this is a quantitative comparison with experimental data with proper statistics. The validation of all-atom simulation methodologies is still a major problem because of the differences between the experimental timescale (from multiple microseconds to seconds) and the theoretical one (from hundreds of nanoseconds to microseconds). To overcome this problem, many approximate coarse-grained methods have been developed during the past decade (2-5). One of them makes use of a physics-based united-residue (UNRES) force field developed in our group over the past years (6-14) (SI Appendix, Fig. S1 and SI Materials and Methods).The folding and unfolding rates are among the most accessible quantitative observables for two-and multistate folding proteins; therefore, a study of protein folding kinetics can bridge microscopic motions and the world of experimental measurements. In analyzing protein folding kinetics, the differential rate equations and their integrated forms become more complex as the num...

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“…Although this seven-residue peptide does not exist in nature, it is one repeat (abcdefg, containing hydrophobic residues at positions a and d and polar residues generally elsewhere) used by proteins to form R-helical coiled coil structures. 86 In addition, it shares the same amino acid length as the Alzheimer's fragment A (16)(17)(18)(19)(20)(21)(22) known to form amyloid fibrils in vitro. 87 Therefore, this peptide represents an ideal system to demonstrate that OPEP, used to study protein aggregation, is not biased toward the formation of -sheets.…”

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confidence: 99%

Replica Exchange Molecular Dynamics Simulations of Coarse-grained Proteins in Implicit Solvent

et al. 2008

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Current approaches aimed at determining the free energy surface of all-atom medium-size proteins in explicit solvent are slow and are not sufficient to converge to equilibrium properties. To ensure a proper sampling of the configurational space, it is preferable to use reduced representations such as implicit solvent and/or coarsegrained protein models, which are much lighter computationally. Each model must be verified, however, to ensure that it can recover experimental structures and thermodynamics. Here we test the coarse-grained implicit solvent OPEP model with replica exchange molecular dynamics (REMD) on six peptides ranging in length from 10 to 28 residues: two alanine-based peptides, the second -hairpin from protein G, the Trp-cage and zinc-finger motif, and a dimer of a coiled coil peptide. We show that REMD-OPEP recovers the proper thermodynamics of the systems studied, with accurate structural description of the -hairpin and Trp-cage peptides (within 1-2 Å from experiments). The light computational burden of REMD-OPEP, which enables us to generate many hundred nanoseconds at each temperature and fully assess convergence to equilibrium ensemble, opens the door to the determination of the free energy surface of larger proteins and assemblies.

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Modification and Optimization of the United-Residue (UNRES) Potential Energy Function for Canonical Simulations. I. Temperature Dependence of the Effective Energy Function and Tests of the Optimization Method with Single Training Proteins

Cited by 191 publications

References 88 publications

Lessons from application of the UNRES force field to predictions of structures of CASP10 targets

Lessons from application of the UNRES force field to predictions of structures of CASP10 targets

Folding kinetics of WW domains with the united residue force field for bridging microscopic motions and experimental measurements

Replica Exchange Molecular Dynamics Simulations of Coarse-grained Proteins in Implicit Solvent

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