title: Ab initio simulation of a 57-residue protein in explicit solvent reproduces the native conformation in the lowest free-energy cluster.
abstract: An enhanced conformational sampling method, multicanonical molecular dynamics (McMD), was applied to the ab intio folding of the 57-residue first repeat of human glutamyl- prolyl-tRNA synthetase (EPRS-R1) in explicit solvent. The simulation started from a fully extended structure of EPRS-R1 and did not utilize prior structural knowledge. A canonical ensemble, which is a conformational ensemble thermodynamically probable at an arbitrary temperature, was constructed by reweighting the sampled structures. Conformational clusters were obtained from the canonical ensemble at 300 K, and the largest cluster (i.e., the lowest free-energy cluster), which contained 34% of the structures in the ensemble, was characterized by the highest similarity to the NMR structure relative to all alternative clusters. This lowest free-energy cluster included native-like structures composed of two anti-parallel α-helices. The canonical ensemble at 300 K also showed that a short Gly-containing segment, which adopts an α-helix in the native structure, has a tendency to be structurally disordered. Atomic-level analyses demonstrated clearly that inter-residue hydrophobic interactions drive the helix formation of the Gly-containing segment, and that increasing the hydrophobic contacts accompanies exclusion of water molecules from the vicinity of this segment. This study has shown, for the first time, that the free-energy landscape of a structurally well-ordered protein of about 60 residues is obtainable with an all atom model in explicit water without prior structural knowledge.
authors.affiliation: Graduate School of Frontier Biosciences, Osaka University, Open Laboratories for Advanced Bioscience and Biotechnology, Suita, Osaka 565-0874, Japan.
authors.forename: Jinzen
authors.initials: J
authors.lastname: Ikebe
authors.forename: Daron M
authors.initials: DM
authors.lastname: Standley
authors.forename: Haruki
authors.initials: H
authors.lastname: Nakamura
authors.forename: Junichi
authors.initials: J
authors.lastname: Higo
mesh_terms: D000465:Algorithms; D020816:Amino Acid Motifs; D000604:Amino Acyl-tRNA Synthetases / Q000737:chemistry*; D003080:Cold Temperature; D006358:Hot Temperature; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D056004:Molecular Dynamics Simulation; D017510:Protein Folding; D055550:Protein Stability; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012997:Solvents; D013816:Thermodynamics
chemical_list: D012997:Solvents; D000604:Amino Acyl-tRNA Synthetases; C415462:glutamyl-prolyl-tRNA synthetase