Investigation of Protein Folding by Coarse-Grained Molecular Dynamics with the UNRES Force Field

被引:79
作者
Maisuradze, Gia G. [1 ]
Senet, Patrick [1 ,2 ]
Czaplewski, Cezary [1 ,3 ]
Liwo, Adam [1 ,3 ]
Scheraga, Harold A. [1 ]
机构
[1] Cornell Univ, Baker Lab Chem & Chem Biol, Ithaca, NY 14853 USA
[2] Univ Bourgogne, Lab Interdisciplinaire Carnot Bourgogne, UMR 5209, CNRS, F-21078 Dijon, France
[3] Univ Gdansk, Fac Chem, PL-80952 Gdansk, Poland
基金
美国国家卫生研究院; 美国国家科学基金会;
关键词
POTENTIAL-ENERGY LANDSCAPE; UNITED-RESIDUE MODEL; MONTE-CARLO-SIMULATION; ACID SIDE-CHAINS; B-DOMAIN; HIERARCHICAL DESIGN; MEAN FORCE; STRUCTURE PREDICTION; ANALYTICAL FORMULAS; POLYPEPTIDE-CHAINS;
D O I
10.1021/jp9117776
中图分类号
O64 [物理化学(理论化学)、化学物理学];
学科分类号
070304 ; 081704 ;
摘要
Coarse-grained molecular dynamics simulations offer a dramatic extension of the time-scale of simulations compared to all-atom approaches. In this article, we describe the use of the physics-based united-residue (UNRES) force field, developed in our laboratory, in protein-structure simulations. We demonstrate that this force field offers about a 4000-times extension of the simulation time scale; this feature arises both from averaging out the fast-moving degrees of freedom and reduction of the cost of energy and force calculations compared to all-atom approaches with explicit solvent. With massively parallel computers, microsecond folding simulation times of proteins containing about 1000 residues can be obtained in days. A straightforward application of canonical UNRES/MD simulations, demonstrated with the example of the N-terminal part of the B-domain of staphylococcal protein A (PDB code: 1BDD, a three-alpha-helix bundle), discerns the folding mechanism and determines kinetic parameters by parallel simulations of several hundred or more trajectories. Use of generalized-ensemble techniques, of which the multiplexed replica exchange method proved to be the most effective, enables us to compute thermodynamics of folding and carry out fully physics-based prediction of protein structure, in which the predicted structure is determined as a mean over the most populated ensemble below the folding-transition temperature. By using principal component analysis of the UNRES folding trajectories of the formin-binding protein WW domain (PDB code: 1EOL; a three-stranded antiparallel beta-sheet) and 1BDD, we identified representative structures along the folding pathways and demonstrated that only a few (low-indexed) principal components can capture the main structural features of a protein-folding trajectory; the potentials of mean force calculated along these essential modes exhibit multiple minima, as opposed to those along the remaining modes that are unimodal. In addition, a comparison between the structures that are representative of the minima in the free-energy profile along the essential collective coordinates of protein folding (computed by principal component analysis) and the free-energy profile projected along the virtual-bond dihedral angles gamma of the backbone revealed the key residues involved in the transitions between the different basins of the folding free-energy profile, in agreement with existing experimental data for 1EOL.
引用
收藏
页码:4471 / 4485
页数:15
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