biostudies-literatureGe YNIDDK NIH HHSNIAID NIH HHSNational Institutes of HealthNIGMS NIH HHSEngineering and Physical Sciences Research Council767-779https://www.ebi.ac.uk/biostudies/studies/S-EPMC9869699biostudies-literatureUnknown36(10)Water plays an important role in mediating protein-ligand interactions. Water rearrangement upon a ligand binding or modification can be very slow and beyond typical timescales used in molecular dynamics (MD) simulations. Thus, inadequate sampling of slow water motions in MD simulations often impairs the accuracy of the accuracy of ligand binding free energy calculations. Previous studies suggest grand canonical Monte Carlo (GCMC) outperforms normal MD simulations for water sampling, thus GCMC has been applied to help improve the accuracy of ligand binding free energy calculations. However, in prior work we observed protein and/or ligand motions impaired how well GCMC performs at water rehydration, suggesting more work is needed to improve this method to handle water sampling. In this workJournal of computer-aided molecular designEnhancing sampling of water rehydration upon ligand binding using variants of grand canonical Monte Carlo.PMC9869699R01 AI108889R01GM108889R01 GM108889EP/R029407/2R01 DK132386R01 GM132386Melling OJDong WEssex JWMobley DLGe YfalseEnhancing sampling of water rehydration upon ligand binding using variants of grand canonical Monte Carlo.Water plays an important role in mediating protein-ligand interactions. Water rearrangement upon a ligand binding or modification can be very slow and beyond typical timescales used in molecular dynamics (MD) simulations. Thus, inadequate sampling of slow water motions in MD simulations often impairs the accuracy of the accuracy of ligand binding free energy calculations. Previous studies suggest grand canonical Monte Carlo (GCMC) outperforms normal MD simulations for water sampling, thus GCMC has been applied to help improve the accuracy of ligand binding free energy calculations. However, in prior work we observed protein and/or ligand motions impaired how well GCMC performs at water rehydration, suggesting more work is needed to improve this method to handle water sampling. In this work2022-01-01T00:00:00Z2022 Oct2026-05-28T01:36:55.851Z2025-04-04T12:48:49.068ZS-EPMC98696993619887410.1007/s10822-022-00479-w