ArticleJournal of chemical theory and computation2020
Accounting for the Central Role of Interfacial Water in Protein-Ligand Binding Free Energy Calculations.
Article in Journal of chemical theory and computation, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed.
- Enhancing Relative Binding Free Energy Calculation with Grand Canonical Monte Carlo, Water-swap Monte Carlo, Terminal-flip Monte Carlo and Replica Exchange Solute Tempering.Journal of chemical theory and computation · 2026Article
- Free energy calculations in molecular modeling: from classical methods to machine learning.Journal of molecular modeling · 2026Review
- A Quadrupolar Fullerene Model System for Benchmarking Enhanced Sampling of Trapped Waters in Free Energy Calculations.The journal of physical chemistry. B · 2026Article
- Molecular Dynamics-Based validation of a quinazoline-based KRAS inhibitor (C9) identified through QSAR-guided discovery.Frontiers in bioinformatics · 2026Article
- MnM-W-MMGBSA: A Computational Strategy to Improve Relative Binding Free Energies of Protein-Protein Interaction Systems.The journal of physical chemistry. B · 2025Article
- Advancing Binding Affinity Calculations: A Non-Equilibrium Simulations Approach for Calculation of Relative Binding Free Energies in Systems with Trapped Waters.Journal of chemical theory and computation · 2025Article
- Template-Based Docking Using Automated Maximum Common Substructure Identification with EnzyDock: Mechanistic and Inhibitor Docking.Journal of chemical information and modeling · 2025Article
- Leveraging a Separation of States Method for Relative Binding Free Energy Calculations in Systems with Trapped Waters.Journal of chemical theory and computation · 2024Article
- Automated Adaptive Absolute Binding Free Energy Calculations.Journal of chemical theory and computation · 2024Article
- Current State of Open Source Force Fields in Protein-Ligand Binding Affinity Predictions.Journal of chemical information and modeling · 2024Article
- Free Energy Density of a Fluid and Its Role in Solvation and Binding.Journal of chemical theory and computation · 2024Article
- Modern Alchemical Free Energy Methods for Drug Discovery Explained.ACS physical chemistry Au · 2023Review
- Comparison of Receptor-Ligand Restraint Schemes for Alchemical Absolute Binding Free Energy Calculations.Journal of chemical theory and computation · 2023Article
- Accelerated Enveloping Distribution Sampling to Probe the Presence of Water Molecules.Journal of chemical theory and computation · 2023Article
- Uncovering water effects in protein-ligand recognition: importance in the second hydration shell and binding kinetics.Physical chemistry chemical physics : PCCP · 2023Article
- Absolute Binding Free Energy Calculations for Buried Water Molecules.Journal of chemical theory and computation · 2022Article
- Enhancing sampling of water rehydration upon ligand binding using variants of grand canonical Monte Carlo.Journal of computer-aided molecular design · 2022Article
- Evaluating the use of absolute binding free energy in the fragment optimisation process.Communications chemistry · 2022Article
- py-MCMD: Python Software for Performing Hybrid Monte Carlo/Molecular Dynamics Simulations with GOMC and NAMD.Journal of chemical theory and computation · 2022Article
- Correction Schemes for Absolute Binding Free Energies Involving Lipid Bilayers.Journal of chemical theory and computation · 2022Article
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Authors and funding
6 authors.
Funding
Abstract
Rigorous binding free energy methods in drug discovery are growing in popularity because of a combination of methodological advances, improvements in computer hardware, and workflow automation. These calculations typically use molecular dynamics (MD) to sample from the Boltzmann distribution of conformational states. However, when part or all of the binding sites is inaccessible to the bulk solvent, the time needed for water molecules to equilibrate between bulk solvent and the binding site can be well beyond what is practical with standard MD. This sampling limitation is problematic in relative binding free energy calculations, which compute the reversible work of converting ligand 1 to ligand 2 within the binding site. Thus, if ligand 1 is smaller and/or more polar than ligand 2, the perturbation may allow additional water molecules to occupy a region of the binding site. However, this change in hydration may not be captured by standard MD simulations and may therefore lead to errors in the computed free energy. We recently developed a hybrid Monte Carlo/MD (MC/MD) method, which speeds up the equilibration of water between bulk solvent and buried cavities, while sampling from the intended distribution of states. Here, we report on the use of this approach in the context of alchemical binding free energy calculations. We find that using MC/MD markedly improves the accuracy of the calculations and also reduces hysteresis between the forward and reverse perturbations, relative to matched calculations using only MD with or without the crystallographic water molecules. The present method is available for use in AMBER simulation software.
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