Molecular ‘time-machines’ to unravel key biological events for drug design

Abstract

Molecular dynamics (MD) has become a routine tool in structural biology andstructure-based drug design (SBDD). MD offers extraordinary insights into thestructures and dynamics of biological systems. With the current capabilities ofhigh-performance supercomputers, it is now possible to perform MD simula-tions of systems as large as millions of atoms and for several nanoseconds time-scale. Nevertheless, many complicated molecular mechanisms, including ligandbinding/unbinding and protein folding, usually take place on timescales of sev-eral microseconds to milliseconds, which are beyond the practical limits of stand-ard MD simulations. Such issues with traditional MD approaches can beeffectively tackled with new generation MD methods, such as enhanced sam-pling MD approaches and coarse-grained MD (CG-MD) scheme. The formeremploy a bias to steer the simulations and reveal biological events that are usu-ally very slow, while the latter groups atoms as interaction beads, thereby redu-cing the system size and facilitating longer MD simulations that can witnesslarge conformational changes in biological systems. In this review, we outlinemany of such advanced MD methods, and discuss how their applications areproviding significant insights into important biological processes, particularlythose relevant to drug design and discovery.