Calculating free energy profiles in biomolecular systems from fast non-equilibrium processes

TL;DR

This paper introduces a rapid non-equilibrium method to calculate free energy profiles in biomolecular systems, enabling efficient modeling of complex dynamics with fewer simulations.

Contribution

It presents a fast, non-equilibrium approach using the FR method to accurately compute potential of mean force and diffusion coefficients with fewer simulations.

Findings

Accurately computed PMFs for deca-alanine and potassium ions in gramicidin A.

Method is approximately ten times faster than traditional PMF calculation techniques.

Provides both free energy profiles and position-dependent diffusion coefficients.

Abstract

Often gaining insight into the functioning of biomolecular systems requires to follow their dynamics along a microscopic reaction coordinate (RC) on a macroscopic time scale, which is beyond the reach of current all atom molecular dynamics (MD) simulations. A practical approach to this inherently multiscale problem is to model the system as a fictitious overdamped Brownian particle that diffuses along the RC in the presence of an effective potential of mean force (PMF) due to the rest of the system. By employing the recently proposed FR method [I. Kosztin et al., J. of Chem. Phys. 124, 064106 (2006)], which requires only a small number of fast nonequilibrium MD simulations of the system in both forward and time reversed directions along the RC, we reconstruct the PMF: (1) of deca-alanine as a function of its end-to-end distance, and (2) that guides the motion of potassium ions through the gramicidin A channel. In both cases the computed PMFs are found to be in good agreement with previous results obtained by different methods. Our approach appears to be about one order of magnitude faster than the other PMF calculation methods and, in addition, it also provides the position dependent diffusion coefficient along the RC. Thus, the obtained PMF and diffusion coefficient can be used in a suitable stochastic model to estimate important characteristics of the studied systems, e.g., the mean folding time of the stretched deca-alanine and the mean diffusion time of the potassium ion through gramicidin A.