A novel multiscale scheme to accelerate atomistic simulations of bio-macromolecules by adaptively driving coarse-grained coordinates.

Abstract

All-atom molecular dynamics (MD) simulations of bio-macromolecules can yield relatively accurate results while suffering from the limitation of insufficient conformational sampling. On the other hand, the coarse-grained (CG) MD simulations efficiently accelerate conformational changes in biomolecules but lose atomistic details and accuracy. Here, we propose a novel multiscale simulation method called the adaptively driving multiscale simulation (ADMS)-it efficiently accelerates biomolecular dynamics by adaptively driving virtual CG atoms on the fly while maintaining the atomistic details and focusing on important conformations of the original system with irrelevant conformations rarely sampled. Herein, the "adaptive driving" is based on the short-time-averaging response of the system (i.e., an approximate free energy surface of the original system), without requiring the construction of the CG force field. We apply the ADMS to two peptides (deca-alanine and Ace-GGPGGG-Nme) and one small protein (HP35) as illustrations. The simulations show that the ADMS not only efficiently captures important conformational states of biomolecules and drives fast interstate transitions but also yields, although it might be in part, reliable protein folding pathways. Remarkably, a ∼100-ns explicit-solvent ADMS trajectory of HP35 with three CG atoms realizes folding and unfolding repeatedly and captures the important states comparable to those from a 398-µs standard all-atom MD simulation.