title: Accelerated molecular dynamics simulations of protein folding.
abstract: Folding of four fast-folding proteins, including chignolin, Trp-cage, villin headpiece and WW domain, was simulated via accelerated molecular dynamics (aMD). In comparison with hundred-of-microsecond timescale conventional molecular dynamics (cMD) simulations performed on the Anton supercomputer, aMD captured complete folding of the four proteins in significantly shorter simulation time. The folded protein conformations were found within 0.2-2.1 Å of the native NMR or X-ray crystal structures. Free energy profiles calculated through improved reweighting of the aMD simulations using cumulant expansion to the second-order are in good agreement with those obtained from cMD simulations. This allows us to identify distinct conformational states (e.g., unfolded and intermediate) other than the native structure and the protein folding energy barriers. Detailed analysis of protein secondary structures and local key residue interactions provided important insights into the protein folding pathways. Furthermore, the selections of force fields and aMD simulation parameters are discussed in detail. Our work shows usefulness and accuracy of aMD in studying protein folding, providing basic references in using aMD in future protein-folding studies.
authors.affiliation: Howard Hughes Medical Institute, University of California at San Diego, La Jolla, California.
authors.forename: Yinglong
authors.initials: Y
authors.lastname: Miao
authors.affiliation: Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, California.|Department of Pharmacology, University of California at San Diego, La Jolla, California.
authors.forename: Ferran
authors.initials: F
authors.lastname: Feixas
authors.affiliation: Howard Hughes Medical Institute, University of California at San Diego, La Jolla, California.
authors.forename: Changsun
authors.initials: C
authors.lastname: Eun
authors.affiliation: Howard Hughes Medical Institute, University of California at San Diego, La Jolla, California.|Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, California.|Department of Pharmacology, University of California at San Diego, La Jolla, California.
authors.forename: J Andrew
authors.initials: JA
authors.lastname: McCammon
mesh_terms: D056004:Molecular Dynamics Simulation; D017510:Protein Folding; D011506:Proteins / Q000737:chemistry*
chemical_list: D011506:Proteins
keywords: accelerated molecular dynamics; enhanced sampling; free energy; protein folding; reweighting