title: Significant Refinement of Protein Structure Models Using a Residue-Specific Force Field.
abstract: An important application of all-atom explicit-solvent molecular dynamics (MD) simulations is the refinement of protein structures from low-resolution experiments or template-based modeling. A critical requirement is that the native structure is stable with the force field. We have applied a recently developed residue-specific force field, RSFF1, to a set of 30 refinement targets from recent CASP experiments. Starting from their experimental structures, 1.0 μs unrestrained simulations at 298 K retain most of the native structures quite well except for a few flexible terminals and long internal loops. Starting from each homology model, a 150 ns MD simulation at 380 K generates the best RMSD improvement of 0.85 Å on average. The structural improvements roughly correlate with the RMSD of the initial homology models, indicating possible consistent structure refinement. Finally, targets TR614 and TR624 have been subjected to long-time replica-exchange MD simulations. Significant structural improvements are generated, with RMSD of 1.91 and 1.36 Å with respect to their crystal structures. Thus, it is possible to achieve realistic refinement of protein structure models to near-experimental accuracy, using accurate force field with sufficient conformational sampling.
authors.affiliation: Laboratory of Computational Chemistry and Drug Design, Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School , Shenzhen, 518055, China.
authors.forename: Sangni
authors.initials: S
authors.lastname: Xun
authors.affiliation: Laboratory of Computational Chemistry and Drug Design, Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School , Shenzhen, 518055, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Jiang
authors.affiliation: Laboratory of Computational Chemistry and Drug Design, Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School , Shenzhen, 518055, China.|College of Chemistry and Molecular Engineering, Peking University , Beijing, 100871, China.
authors.forename: Yun-Dong
authors.initials: YD
authors.lastname: Wu
mesh_terms: D056004:Molecular Dynamics Simulation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry*; D013696:Temperature
chemical_list: D011506:Proteins