Enhancing Side Chain Rotamer Sampling Using Nonequilibrium Candidate Monte Carlo

Abstract

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 is 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.

Energetics of Storage and Diffusion of Water and Cyclo-Octasulfur for a Nonpolar Cavity of RHCC Tetrabrachion by Molecular Dynamics Simulations

“…The simulation time of 1 ns which was employed in the current investigation raises the question of whether sufficient time was allowed to achieve equilibration perpendicular to the reaction coordinate, particularly among rotameric states of side chains. Several recent publications have directly addressed the difficulties associated with extending simulation runs to achieve sufficient sampling of rotameric transitions which, in principle, can involve timescales ranging from ps to several hundred ns depending on the local environment [ 33 , 34 ]. Given this broad spectrum of potential equilibration times and the consequent uncertainty in defining an appropriate simulation time, these investigations applied PMF methods to calculate corrections to the free energy arising from rotamer transitions by pulling the side chain between its stable rotameric orientations.…”

Challenges Encountered Applying Equilibrium and Non-Equilibrium Binding Free Energy Calculations

“…However, better solutions are needed to make alchemical FEC more general and robust. In the long-term, greater use of enhanced sampling techniques is likely needed, such as perhaps BLUES-like moves 47,62 to accelerate side chain sampling.…”

“…Approaches to overcome these sampling problems include the use of enhanced sampling techniques, like HREX or incorporating BLUES-like side chain moves. 47,62…”

Enhancing water sampling of buried binding sites using nonequilibrium candidate Monte Carlo

“…This water hopping approach can be used to find areas that are likely to be populated by waters in protein binding sites and sample water rearrangements potentially more efficiently than traditional MD. Water hopping moves could be combined with additional types of BLUES moves such as ligand [19,40] or sidechain [11] rotational moves for broader applications.…”

“…BLUES (Binding Modes of Ligands Using Enhanced Sampling), which combines NCMC with classical MD, was originally created to enhance the sampling of ligand binding modes [19], but has begun applying the same techniques to enhance sampling of other degrees of freedom also important in ligand binding, such as sidechain rearrangements [11] and, here, water motions. In BLUES, NCMC moves are executed through a switching protocol that is comprised of a series of perturbation and propagation/relaxation steps involving structural and dynamic degrees of freedom [34].…”