title: Virtual-system-coupled adaptive umbrella sampling to compute free-energy landscape for flexible molecular docking.
abstract: A novel enhanced conformational sampling method, virtual-system-coupled adaptive umbrella sampling (V-AUS), was proposed to compute 300-K free-energy landscape for flexible molecular docking, where a virtual degrees of freedom was introduced to control the sampling. This degree of freedom interacts with the biomolecular system. V-AUS was applied to complex formation of two disordered amyloid-β (Aβ30-35 ) peptides in a periodic box filled by an explicit solvent. An interpeptide distance was defined as the reaction coordinate, along which sampling was enhanced. A uniform conformational distribution was obtained covering a wide interpeptide distance ranging from the bound to unbound states. The 300-K free-energy landscape was characterized by thermodynamically stable basins of antiparallel and parallel β-sheet complexes and some other complex forms. Helices were frequently observed, when the two peptides contacted loosely or fluctuated freely without interpeptide contacts. We observed that V-AUS converged to uniform distribution more effectively than conventional AUS sampling did.
authors.affiliation: Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Higo
authors.affiliation: Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Bhaskar
authors.initials: B
authors.lastname: Dasgupta
authors.affiliation: Technology Research Association for Next Generation Natural Products Chemistry, 2-3-26 Aomi, Koto-Ku, Tokyo, 135-0064, Japan.|Information, Mathematical Science and Bioinformatics Co., Ltd., 4-21-1, Higashiikebukuro, Toshima-ku, Tokyo, 170-0013, Japan.
authors.forename: Tadaaki
authors.initials: T
authors.lastname: Mashimo
authors.affiliation: Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Kota
authors.initials: K
authors.lastname: Kasahara
authors.affiliation: Molecular Profiling Research Center for Drug Discovery (molprof), National Institute of Advanced Industrial Science and Technology (AIST), 2-3-26 Aomi, Koto-ku, Tokyo, 135-0064, Japan.
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Fukunishi
authors.affiliation: Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Haruki
authors.initials: H
authors.lastname: Nakamura
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry*; D062105:Molecular Docking Simulation; D013816:Thermodynamics
chemical_list: D016229:Amyloid beta-Peptides
keywords: adaptive umbrella; flexible docking; free-energy landscape; multicanonical; virtual system