Enhanced molecular dynamics sampling of drug target conformations

Computational docking and virtual screening are two main important methods employed in structure‐based drug design. Unlike the traditional approach that allows docking of a flexible ligand against a handful of receptor structures, receptor flexibility has now been appreciated and increasingly incorporated in computer‐aided docking. Using a diverse set of receptor conformations increases the chances of finding potential drugs and inhibitors. Molecular dynamics (MD) is greatly useful to generate various receptor conformations. However, the diversity of the structures of the receptor, which is usually much larger than the ligand, depends on the sampling efficiency of MD. Enhanced sampling methods based on accelerated molecular dynamics (aMD) can alleviate the sampling limitation of conventional MD and aid in representation of the phase space to a much greater extent. RaMD‐db, a variant of aMD that applies boost potential to the rotatable dihedrals and non‐bonded diffusive degrees of freedom has been proven to reproduce the equilibrium properties more accurately and efficiently than aMD. Here, we discuss recent advances in the aMD methodology and review the applicability of RaMD‐db as an enhanced sampling method. RaMD‐db is shown to be able to generate a broad distribution of structures of a drug target, Cyclophilin A. These structures that have never been observed previously in very long conventional MD can be further used for structure‐based computer‐aided drug discovery, and docking, and thus, in the identification and design of potential novel inhibitors. © 2015 Wiley Periodicals, Inc. Biopolymers 105: 35–42, 2016.