title: Investigation of protein folding by coarse-grained molecular dynamics with the UNRES force field.
abstract: 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: 1E0L; 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 1E0L .
authors.affiliation: Baker Laboratory of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853-1301, USA.
authors.forename: Gia G
authors.initials: GG
authors.lastname: Maisuradze
authors.forename: Patrick
authors.initials: P
authors.lastname: Senet
authors.forename: Cezary
authors.initials: C
authors.lastname: Czaplewski
authors.forename: Adam
authors.initials: A
authors.lastname: Liwo
authors.forename: Harold A
authors.initials: HA
authors.lastname: Scheraga
mesh_terms: D000465:Algorithms; D000818:Animals; D001426:Bacterial Proteins / Q000737:chemistry; D002352:Carrier Proteins / Q000737:chemistry; D007700:Kinetics; D051379:Mice; D015233:Models, Statistical; D056004:Molecular Dynamics Simulation; D025341:Principal Component Analysis; D011485:Protein Binding; D017510:Protein Folding; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry*; D012399:Rotation; D012997:Solvents / Q000737:chemistry; D013211:Staphylococcus aureus / Q000737:chemistry; D013816:Thermodynamics; D035602:Transcriptional Elongation Factors
chemical_list: D001426:Bacterial Proteins; D002352:Carrier Proteins; D011506:Proteins; D012997:Solvents; C473940:Tcerg1 protein, mouse; D035602:Transcriptional Elongation Factors