Enhancing QM/MM molecular dynamics sampling in explicit environments via an orthogonal-space-random-walk-based strategy.

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.