Effectively explore metastable states of proteins by adaptive nonequilibrium driving simulations.

Abstract

Nonequilibrium drivings applied in molecular dynamics (MD) simulations can efficiently extend the visiting range of protein conformations, but might compel systems to go far away from equilibrium and thus mainly explore irrelevant conformations. Here we propose a general method, called adaptive nonequilibrium simulation (ANES), to automatically adjust the external driving on the fly, based on the feedback of the short-time average response of system. Thus, the ANES approximately keeps the local equilibrium but efficiently accelerates the global motion. We illustrate the capability of the ANES in highly efficiently exploring metastable conformations in the deca-alanine peptide and find that the 0.2-μs ANES approximately captures the important states and folding and unfolding pathways in the HP35 solution by comparing with the result of the recent 398-μs equilibrium MD simulation on Anton [S. Piana et al., Proc. Natl. Acad. Sci. USA 109, 17845 (2012)PNASA60027-842410.1073/pnas.1201811109].