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Enhancing Sidechain Rotamer Sampling Using Non-Equilibrium Candidate Monte Carlo

revised on 19.01.2019 and posted on 21.01.2019 by Kalistyn H. Burley, Samuel C. Gill, Nathan M. Lim, David Mobley
Molecular simulations are a valuable tool for studying biomolecular motions and thermodynamics. However, such motions can be slow compared to simulation timescales, yet critical. Specifically, adequate sampling of sidechain motions in protein binding pockets proves crucial for obtaining accurate estimates of ligand binding free energies from molecular simulations. The timescale of sidechain 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 non-equilibrium candidate Monte Carlo (NCMC)/molecular dynamics (MD) method to enhance sampling of sidechain rotamers. The NCMC portion of our method applies a switching protocol wherein the steric and electrostatic interactions between target sidechain 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 sidechain using our approach and compare it to that of traditional molecular dynamics simulations. Here, we show that our NCMC/MD method substantially enhances sidechain 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 sidechain sampling in molecular simulations.


NIH 1R01GM108889-01, NIH T32GM108561, NSF CHE 1352608


Email Address of Submitting Author


University of California, Irvine


United States

ORCID For Submitting Author


Declaration of Conflict of Interest

DLM serves on the scientific advisory board of OpenEye Scientific Software and is an Open Science Fellow with Silicon Therapeutics. As far as we are aware there is no conflict of interest with this work.

Version Notes

Updates to improve clarity and add some additional details, as per peer review process.



Read the published paper

in Journal of Chemical Theory and Computation

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