Physics-based protein-structure prediction using a hierarchical protocol based on the UNRES force field: Assessment in two blind tests

Ołdziej, Stanisław; Czaplewski, Cezary; Liwo, Adam; Chinchio, Maurizio; Nanias, Marian; Vila, Jorge A.; Khalili, Mey; Arnautova, Yelena A.; Jagielska, Anna; Makowski, Mariusz; Schafroth, Heather D.; Kaźmierkiewicz, Rajmund; Ripoll, Daniel R.; Pillardy, Jarosław; Saunders, Jeff; Kang, Young Kee; Gibson, Kenneth D.; Scheraga, Harold A.

doi:10.1073/pnas.0502655102

Cited by 136 publications

(119 citation statements)

References 50 publications

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“…That the result obtained for T0663 was not a fortuitous incident is demonstrated by other good results obtained during the CASP10 exercise (Fig. 4) and in previous CASP exercises (18,19,37). It can, therefore, be concluded that our physics-based coarse-grained approach has substantial power to predict protein structures.…”

Section: Discussionmentioning

confidence: 53%

“…Examples are, e.g., targets T0063 and T0215 of the 3rd Community Wide Experiment on the Critical Assessment of Techniques for Protein Structure Prediction (CASP3) and CASP6 experiments, respectively, whose cores are simple three α-helix bundle folds, for which threading found mirror-image folds. Conversely, correct folds were predicted by our physics-based approach based on the physics-based coarse-grained force field (United Residue, UNRES) (18,19).…”

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: Discussionmentioning

confidence: 53%

Section: Significancementioning

confidence: 99%

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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“…In connection with the efficient conformational space annealing (CSA) method 50,51 of global optimization, UNRES is able to predict the structures of real-size proteins without ancillary information from structural databases. 39,43,48,49,52,53 For all these reasons, UNRES appears to be a good mezoscopic force field with which the folding pathways of proteins can be studied in real time. Therefore, our present work is aimed at implementation of the UNRES force field in a molecular dynamics algorithm.…”

Section: Introductionmentioning

confidence: 99%

Molecular Dynamics with the United-Residue Model of Polypeptide Chains. I. Lagrange Equations of Motion and Tests of Numerical Stability in the Microcanonical Mode

et al. 2005

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The Lagrange formalism was implemented to derive the equations of motion for the physics-based united-residue (UNRES) force field developed in our laboratory. The C α… C α and C α… SC (SC denoting a side-chain center) virtual-bond vectors were chosen as variables. The velocity Verlet algorithm was adopted to integrate the equations of motion. Tests on the unblocked Ala 10 polypeptide showed that the algorithm is stable in short periods of time up to the time step of 1.467 fs; however, even with the shorter time step of 0.489 fs, some drift of the total energy occurs because of momentary jumps of the acceleration. These jumps are caused by numerical instability of the forces arising from the U rot component of UNRES that describes the energetics of side-chain-rotameric states. Test runs on the Gly 10 sequence (in which U rot is not present) and on the Ala 10 sequence with U rot replaced by a simple numerically stable harmonic potential confirmed this observation; oscillations of the total energy were observed only up to the time step of 7.335 fs, and some drift in the total energy or instability of the trajectories started to appear in long-time (2 ns and longer) trajectories only for the time step of 9.78 fs. These results demonstrate that the present U rot components (which are statistical potentials derived from the Protein Data Bank) must be replaced with more numerically stable functions; this work is under way in our laboratory. For the purpose of our present work, a nonsymplectic variable-time-step algorithm was introduced to reduce the energy drift for regular polypeptide sequences. The algorithm scales down the time step at a given point of a trajectory if the maximum change of acceleration exceeds a selected cutoff value. With this algorithm, the total energy is reasonably conserved up to a time step of 2.445 fs, as tested on the unblocked Ala 10 polypeptide. We also tried a symplectic multiple-time-step reversible RESPA algorithm and achieved satisfactory energy conservation for time steps up to 7.335 fs. However, at present, it appears that the reversible RESPA algorithm is several times more expensive than the variable-time-step algorithm because of the necessity to perform additional matrix multiplications. We also observed that, because Ala 10 folds and unfolds within picoseconds in the microcanonical mode, this suggests that the effective (event-based) time unit in UNRES dynamics is much larger than that of all-atom dynamics because of averaging over the fast-moving degrees of freedom in deriving the UNRES potential.

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“…In the UNRES model, [17][18][19][20][21][22][23]25,27,31,32,37,38,[56][57][58] a polypeptide chain is represented by a sequence of α-carbon (C α ) atoms linked by virtual bonds with attached united side chains (SC) and united peptide groups (p). Each united peptide group is located in the middle between two consecutive α-carbons.…”

Section: The Unres Force Field For Global Optimizationmentioning

confidence: 99%

“…These conclusions were extended in our further work 27,31 to an off-lattice protein representation. Application of the hierarchical procedure using four training proteins [the LysM domain from E. coli (an α + β protein; PDB code: 1E0G 33 ), the Fbp28Ww domain from Mus musculus (a β protein; PDB code: 1E0L 34 ), the albumin-binding GA module (an α protein; PDB code: 1GAB 35 ), and the IgG-binding domain from streptococcal protein G (an α + β protein; PDB code: 1IGD 36 )] resulted in a force field capable of ab initio prediction of proteins of different structural classes with good accuracy, 32 as demonstrated further 37 in the CASP6 experiment in which we predicted complete structures of five proteins and large portions of structure of other targets.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2006

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We report the modification and parameterization of the united-residue (UNRES) force field for energy-based protein-structure prediction and protein-folding simulations. We tested the approach on three training proteins separately: 1E0L (β), 1GAB (α), and 1E0G (α + β). Heretofore, the UNRES force field had been designed and parameterized to locate native-like structures of proteins as global minima of their effective potential-energy surfaces, which largely neglected the conformational entropy because decoys composed of only lowest-energy conformations were used to optimize the force field. Recently, we developed a mesoscopic dynamics procedure for UNRES, and applied it with success to simulate protein folding pathways. How ever, the force field turned out to be largely biased towards α-helical structures in canonical simulations because the conformational entropy had been neglected in the parameterization. We applied the hierarchical optimization method developed in our earlier work to optimize the force field, in which the conformational space of a training protein is divided into levels each corresponding to a certain degree of native-likeness. The levels are ordered according to increasing native-likeness; level 0 corresponds to structures with no native-like elements and the highest level corresponds to the fully native-like structures. The aim of optimization is to achieve the order of the free energies of levels, decreasing as their native-likeness increases. The procedure is iterative, and decoys of the training protein(s) generated with the energy-function parameters of the preceding iteration are used to optimize the force field in a current iteration. We applied the multiplexing replica exchange molecular dynamics (MREMD) method, recently implemented in UNRES, to generate decoys; with this modification, conformational entropy is taken into account. Moreover, we optimized the free-energy gaps between levels at temperatures corresponding to a predominance of folded or unfolded structures, as well as to structures at the putative folding-transition temperature, changing the sign of the gaps at the transition temperature. This enabled us to obtain force fields characterized by a single peak in the heat capacity at the transition temperature. Furthermore, we introduced temperature dependence to the UNRES force field; this is consistent with the fact that it is a free-energy and not a potential-energy function.

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Physics-based protein-structure prediction using a hierarchical protocol based on the UNRES force field: Assessment in two blind tests

Cited by 136 publications

References 50 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

Molecular Dynamics with the United-Residue Model of Polypeptide Chains. I. Lagrange Equations of Motion and Tests of Numerical Stability in the Microcanonical Mode

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

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