title: Enhancing QM/MM molecular dynamics sampling in explicit environments via an orthogonal-space-random-walk-based strategy.
abstract: Accurate prediction of molecular conformations in explicit environments, such as aqueous solution and protein interiors, can facilitate our understanding of various molecular recognition processes. Most computational approaches are limited as a result of their compromised choices between the underlying energy model and the sampling length. Taking advantage of a recent second-order generalized ensemble scheme [e.g., the orthogonal space random walk (OSRW) strategy], which can synergistically accelerate the motion of a focused region and its coupled environmental response, we are presenting a QM/MM (combined quantum mechanical/molecular mechanical)-based molecular dynamics sampling technique to explore molecular conformational landscapes in explicit environments. The present QM/MM potential scaling-based OSRW sampling scheme is employed to study the binding of DMSO to the FKBP12 protein, the conformation distribution of a novel mercaptosulfonamide inhibitor in aqueous solution, and its binding poses in zinc-containing matrix metalloproteinase-9 (MMP-9). As demonstrated, the present QM/MM second-order generalized ensemble sampling technique enables feasible usage of the QM/MM model to sample molecular conformations in condensed environments.
authors.affiliation: Institute of Molecular Biophysics, Florida State University, Tallahassee, Florida 32306, USA.
authors.forename: Donghong
authors.initials: D
authors.lastname: Min
authors.forename: Mengen
authors.initials: M
authors.lastname: Chen
authors.forename: Lianqing
authors.initials: L
authors.lastname: Zheng
authors.forename: Yonghao
authors.initials: Y
authors.lastname: Jin
authors.forename: Martin A
authors.initials: MA
authors.lastname: Schwartz
authors.forename: Qing-Xiang Amy
authors.initials: QX
authors.lastname: Sang
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
mesh_terms: D001665:Binding Sites; D004121:Dimethyl Sulfoxide / Q000737:chemistry; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D008962:Models, Theoretical; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D011789:Quantum Theory; D013449:Sulfonamides / Q000737:chemistry; D022061:Tacrolimus Binding Protein 1A / Q000737:chemistry* / Q000378:metabolism; D014867:Water / Q000737:chemistry
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D013449:Sulfonamides; D014867:Water; D020780:Matrix Metalloproteinase 9; D022061:Tacrolimus Binding Protein 1A; D004121:Dimethyl Sulfoxide