Enhanced sampling enables binding site water reorganization in polarizable absolute binding free energy calculations
4 affiliations
- 1Laboratoire de Chimie Théorique, Sorbonne Université, Paris, Cedex 05, France
- 2Sorbonne Université
- 3Advanced Research Department, Qubit Pharmaceuticals, Paris, 75014, France
- 4Qubit Pharmaceuticals (France)
Abstract
Water molecules play a critical role in mediating protein-ligand interactions by forming hydrogen-bonding networks and contributing to ligand solvation. However, their behavior—ranging from rapid solvent exchange to persistent occupancy of buried sites—makes accurate binding free-energy estimation with molecular dynamics challenging. Inadequate sampling of water reorganization can bias computed affinities and obscure key interactions by preventing representative hydration states during calculations. To address this, we employ the polarizable AMOEBA force field together with Lambda-ABF-OPES, an integrated enhanced-sampling framework combining lambda-dynamics, multiple-walker adaptive biasing force, and on-the-fly probability enhanced sampling. AMOEBA provides a polarizable description of protein–ligand, ligand–water, and protein–water interactions, while the dynamic alchemical coordinate and adaptive biasing facilitate exploration of coupled ligand-pocket-solvent configurations during ligand decoupling. This construction allows water exchange, binding-site rehydration and solvent reorganization to emerge along the alchemical pathway without explicitly biasing water-based collective variables. Applied to five protein-ligand complexes spanning buried and semi-buried environments, the approach yields binding affinities in good agreement with experiment and captures relevant water-mediated reorganization to provide reproducible absolute binding free energies.
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BibTeX
@article{blazhynska2026enhanced,
title = {{Enhanced sampling enables binding site water reorganization in polarizable absolute binding free energy calculations}},
author = {Marharyta Blazhynska and Narjes Ansari and Louis Lagardère and Jean‐Philip Piquemal},
journal = {Communications Chemistry},
year = {2026},
month = oct,
doi = {10.1038/s42004-026-02253-7},
url = {https://www.nature.com/articles/s42004-026-02253-7},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Enhanced sampling enables binding site water reorganization in polarizable absolute binding free energy calculations
AU - Marharyta Blazhynska
AU - Narjes Ansari
AU - Louis Lagardère
AU - Jean‐Philip Piquemal
PY - 2026
DA - 2026/10/12
JO - Communications Chemistry
DO - 10.1038/s42004-026-02253-7
UR - https://www.nature.com/articles/s42004-026-02253-7
AB - Water molecules play a critical role in mediating protein-ligand interactions by forming hydrogen-bonding networks and contributing to ligand solvation. However, their behavior—ranging from rapid solvent exchange to persistent occupancy of buried sites—makes accurate binding free-energy estimation with molecular dynamics challenging. Inadequate sampling of water reorganization can bias computed affinities and obscure key interactions by preventing representative hydration states during calculations. To address this, we employ the polarizable AMOEBA force field together with Lambda-ABF-OPES, an integrated enhanced-sampling framework combining lambda-dynamics, multiple-walker adaptive biasing force, and on-the-fly probability enhanced sampling. AMOEBA provides a polarizable description of protein–ligand, ligand–water, and protein–water interactions, while the dynamic alchemical coordinate and adaptive biasing facilitate exploration of coupled ligand-pocket-solvent configurations during ligand decoupling. This construction allows water exchange, binding-site rehydration and solvent reorganization to emerge along the alchemical pathway without explicitly biasing water-based collective variables. Applied to five protein-ligand complexes spanning buried and semi-buried environments, the approach yields binding affinities in good agreement with experiment and captures relevant water-mediated reorganization to provide reproducible absolute binding free energies.
SN - 2399-3669
ER -