Configurational Sampling of All-Atom Solvated Membranes Using Hybrid Nonequilibrium Molecular Dynamics Monte Carlo...

All-atom simulations are a powerful approach to study the structure and dynamics of biological membranes. However, sampling the atomic configurations of inhomogeneous membranes can be challenging due to the slow lateral diffusion of the various constituents. To address this issue, a hybrid nonequilibrium molecular dynamics Monte Carlo (neMD/MC) simulation method is proposed in which randomly chosen lipid molecules are swapped to generate configurations that are subsequently accepted or rejected according to a Metropolis criterion based on the alchemical work for the attempted swap calculated via a short trajectory. A dual-topology framework constraining the common atoms of the exchanging molecules yields a good acceptance probability using switching trajectories as short as 10 ps. The performance of the hybrid neMD/MC algorithm and its ability to sample the distribution of lipids near a transmembrane helix carrying a net charge are illustrated for a binary mixture of charged and zwitterionic lipids.