Enhancing Side Chain Rotamer Sampling Using Nonequilibrium Candidate Monte Carlo

Molecular simulations are a valuable
tool for studying biomolecular
motions and thermodynamics. However, such motions can be slow compared
to simulation time scales, yet critical. Specifically, adequate sampling
of side chain motions in protein binding pockets is crucial for obtaining
accurate estimates of ligand binding free energies from molecular
simulations. The time scale of side chain rotamer flips can range
from a few ps to several hundred ns or longer, particularly in crowded
environments like the interior of proteins. Here, we apply a mixed
nonequilibrium candidate Monte Carlo (NCMC)/molecular dynamics (MD)
method to enhance sampling of side chain rotamers. The NCMC portion
of our method applies a switching protocol wherein the steric and
electrostatic interactions between target side chain atoms and the
surrounding environment are cycled off and then back on during the
course of a move proposal. Between NCMC move proposals, simulation
of the system continues via traditional molecular dynamics. Here,
we first validate this approach on a simple, solvated valine-alanine
dipeptide system and then apply it to a well-studied model ligand
binding site in T4 lysozyme L99A. We compute the rate of rotamer transitions
for a valine side chain using our approach and compare it to that
of traditional molecular dynamics simulations. Here, we show that
our NCMC/MD method substantially enhances side chain sampling, especially
in systems where the torsional barrier to rotation is high (≥10
kcal/mol). These barriers can be intrinsic torsional barriers or steric
barriers imposed by the environment. Overall, this may provide a promising
strategy to selectively improve side chain sampling in molecular simulations.