Enhanced molecular dynamics sampling of drug target conformations

Abstract

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.

Experimental conformational energy maps of proteins and peptides

“…Simulations of protein structures and their interactions with ligands play a role in a variety of application areas such as computer aided structure‐based drug discovery, refinement of X‐ray crystallographic, and NMR data, reaction mechanisms, protein folding pathways, and free energy perturbation studies . Most simulations are carried out using either molecular mechanics (MM) force fields alone or with a combination of quantum mechanics and molecular mechanics methods (QM/MM).…”

Predicting binding modes of reversible peptide-based inhibitors of falcipain-2 consistent with structure-activity relationships

“…Remarkably, by employing aMD simulations, it was possible to sample molecular events usually prohibitive for cMD simulations in the scale of hundreds of nanoseconds, as has been profusely discussed elsewhere . In fact, the discarded poses of compounds 68 , 79 , and 81 (Figs.…”

Molecular dynamics-driven drug discovery: leaping forward with confidence

“…Several enhanced sampling approaches have been developed, including metadynamics, replica exchange molecular dynamics (REMD), random acceleration molecular dynamics (RAMD), steered molecular dynamics (SMD) and adaptive bias force steering (ABFS). There are a number of reviews, for example see references [145][146][147], discussing the applications of these methods in SBDD. Alternatively, coarse-grained MD (CG-MD) [148], which reduces the degrees of freedom in large systems by clustering groups of atoms into CG beads, has been developed to deal with large dynamic changes in more complex macromolecules.…”