title: Discrete molecular dynamics: an efficient and versatile simulation method for fine protein characterization.
abstract: Until now it has been impractical to observe protein folding in silico for proteins larger than 50 residues. Limitations of both force field accuracy and computational efficiency make the folding problem very challenging. Here we employ discrete molecular dynamics (DMD) simulations with an all-atom force field to fold fast-folding proteins. We extend the DMD force field by introducing long-range electrostatic interactions to model salt-bridges and a sequence-dependent semiempirical potential accounting for natural tendencies of certain amino acid sequences to form specific secondary structures. We enhance the computational performance by parallelizing the DMD algorithm. Using a small number of commodity computers, we achieve sampling quality and folding accuracy comparable to the explicit-solvent simulations performed on high-end hardware. We demonstrate that DMD can be used to observe equilibrium folding of villin headpiece and WW domain, study two-state folding kinetics, and sample near-native states in ab initio folding of proteins of ∼100 residues.
authors.affiliation: Department of Biochemistry and Biophysics, School of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599, United States.
authors.forename: David
authors.initials: D
authors.lastname: Shirvanyants
authors.forename: Feng
authors.initials: F
authors.lastname: Ding
authors.forename: Douglas
authors.initials: D
authors.lastname: Tsao
authors.forename: Srinivas
authors.initials: S
authors.lastname: Ramachandran
authors.forename: Nikolay V
authors.initials: NV
authors.lastname: Dokholyan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry; D000465:Algorithms; D000595:Amino Acid Sequence; D000818:Animals; D010582:Bacteriophage lambda / Q000737:chemistry; D002417:Cattle; D002645:Chickens; D006801:Humans; D008840:Microfilament Proteins / Q000737:chemistry; D056004:Molecular Dynamics Simulation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry*; D012097:Repressor Proteins / Q000737:chemistry; D025801:Ubiquitin / Q000737:chemistry; D054334:Viral Regulatory and Accessory Proteins / Q000737:chemistry; D018909:src Homology Domains
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D008840:Microfilament Proteins; D011506:Proteins; D012097:Repressor Proteins; D025801:Ubiquitin; D054334:Viral Regulatory and Accessory Proteins; C016649:phage repressor proteins; C026615:villin