ArticleJournal of chemical theory and computation2019
Enhancing Side Chain Rotamer Sampling Using Nonequilibrium Candidate Monte Carlo.
Article in Journal of chemical theory and computation, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed.
- An Automated Workflow for Diagnosing Sampling Issues Caused by Slow Torsional Motions in Molecular Simulations.Journal of chemical information and modeling · 2026Article
- Accurate conformational ensembles of intrinsically disordered proteins using reweighting based on NMR chemical shifts.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Accelerating fragment-based drug discovery using grand canonical nonequilibrium candidate Monte Carlo.Nature communications · 2025Article
- Impact of Varying Velocities and Solvation Boxes on Alchemical Free-Energy Simulations.Journal of chemical information and modeling · 2025Article
- Kinetics-Based State Definitions for Discrete Binding Conformations of T4 L99A in MD via Markov State Modeling.Journal of chemical information and modeling · 2024Article
- Parsing Dynamics of Protein Backbone NH and Side-Chain Methyl Groups using Molecular Dynamics Simulations.Journal of chemical theory and computation · 2024Article
- The SAMPL9 host-guest blind challenge: an overview of binding free energy predictive accuracy.Physical chemistry chemical physics : PCCP · 2024Article
- Enhanced Grand Canonical Sampling of Occluded Water Sites Using Nonequilibrium Candidate Monte Carlo.Journal of chemical theory and computation · 2023Article
- An overview of the SAMPL8 host-guest binding challenge.Journal of computer-aided molecular design · 2022Article
- Enhancing Ligand and Protein Sampling Using Sequential Monte Carlo.Journal of chemical theory and computation · 2022Article
- Enhancing Sampling of Water Rehydration on Ligand Binding: A Comparison of Techniques.Journal of chemical theory and computation · 2022Article
- Temperature artifacts in protein structures bias ligand-binding predictions.Chemical science · 2021Article
- Challenges Encountered Applying Equilibrium and Nonequilibrium Binding Free Energy Calculations.The journal of physical chemistry. B · 2021Article
- Enhancing water sampling of buried binding sites using nonequilibrium candidate Monte Carlo.Journal of computer-aided molecular design · 2021Article
- Reversibly Sampling Conformations and Binding Modes Using Molecular Darting.Journal of chemical theory and computation · 2021Article
- Sampling Conformational Changes of Bound Ligands Using Nonequilibrium Candidate Monte Carlo and Molecular Dynamics.Journal of chemical theory and computation · 2020Article
- Computational reconstruction of atomistic protein structures from coarse-grained models.Computational and structural biotechnology journal · 2020Review
- Middle-way flexible docking: Pose prediction using mixed-resolution Monte Carlo in estrogen receptor α.PloS one · 2019Article
- Energetics of Storage and Diffusion of Water and Cyclo-Octasulfur for a Nonpolar Cavity of RHCC Tetrabrachion by Molecular Dynamics Simulations.Computational and structural biotechnology journal · 2019Article
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Authors and funding
4 authors.
Funding
Abstract
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.
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Registered trials
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