All you need is water: Converging ligand binding simulations with hydration collective variables

Article Article scientifique Article All you need is water: Converging ligand binding simulations with hydration collective variables eng 2025-10-23 2025-10-28 author Schulze Marc 0009-0007-5175-5402 School of Pharmaceutical Sciences, University of Geneva, Rue Michel-Servet 1, 1206 Genève, Switzerland. 406695 Section des sciences pharmaceutiques (FARMA) author Khakhula Tetiana 0009-0001-2551-3254 Department of Physical Chemistry, Sciences II, University of Geneva, Genève 1211, Switzerland. 409987 Chimie physique (groupe 8) (CHIF8) author Piasentin Nicola 0000-0003-2760-4640 School of Pharmaceutical Sciences, University of Geneva, Rue Michel-Servet 1, 1206 Genève, Switzerland.,Institute of Pharmaceutical Sciences of Western Switzerland (ISPSO), University of Geneva, 1206 Genève, Switzerland.,Swiss Institute of Bioinformatics, University of Geneva, 1206 Genève, Switzerland. 417881 Section des sciences pharmaceutiques (FARMA) author Aureli Simone 0000-0002-4938-8603 School of Pharmaceutical Sciences, University of Geneva, Rue Michel-Servet 1, 1206 Genève, Switzerland.,Institute of Pharmaceutical Sciences of Western Switzerland (ISPSO), University of Geneva, 1206 Genève, Switzerland.,Swiss Institute of Bioinformatics, University of Geneva, 1206 Genève, Switzerland. 984101 Section des sciences pharmaceutiques (FARMA) author Rizzi Valerio 0000-0001-5126-8996 School of Pharmaceutical Sciences, University of Geneva, Rue Michel-Servet 1, 1206 Genève, Switzerland.,Institute of Pharmaceutical Sciences of Western Switzerland (ISPSO), University of Geneva, 1206 Genève, Switzerland.,Swiss Institute of Bioinformatics, University of Geneva, 1206 Genève, Switzerland. 402294 Section des sciences pharmaceutiques (FARMA) author Gervasio Francesco Luigi 0000-0003-4831-5039 School of Pharmaceutical Sciences, University of Geneva, Rue Michel-Servet 1, 1206 Genève, Switzerland.,Institute of Pharmaceutical Sciences of Western Switzerland (ISPSO), University of Geneva, 1206 Genève, Switzerland.,Swiss Institute of Bioinformatics, University of Geneva, 1206 Genève, Switzerland.,Department of Chemistry, University College London, London WC1E 6BT, United Kingdom. 931636 Section des sciences pharmaceutiques (FARMA) 164111 10.1063/5.0287856 41128318 0021-9606 https://pubs.aip.org/jcp/article/163/16/164111/3368948/All-you-need-is-water-Converging-ligand-binding Selecting appropriate collective variables (CVs) is a crucial bottleneck in enhanced sampling molecular dynamics simulations. Although progress has been made with data-driven and intuition-based approaches, optimal CVs remain system-specific. Meanwhile, simple geometric descriptors are still widely used due to their transferability. A promising, yet under-explored, candidate for a more efficient CV is solvation. Indeed, despite its central role in ligand binding and folding, the complexity of solvent behavior has hindered its widespread use. Here, we introduce a data-driven and automatic strategy to construct robust solvation-based CVs. Our method identifies critical hydration sites by analyzing the radial distribution function of water around a ligand. Remarkably, using only these hydration CVs within on-the-fly probability enhanced sampling simulations, we successfully converge the binding free energy landscapes for a series of host-guest systems. These landscapes show excellent agreement with those from more computationally expensive benchmark methods. We further demonstrate that the choice of where to bias water is key to efficient convergence, providing clear guidelines for implementation. This work not only underscores the central role of water in molecular recognition but also offers a powerful and generalizable framework for enhancing the sampling of complex biomolecular events. Dewey 615 Swiss National Science Foundation Understanding and Modelling Cryptic Binding Pockets for Biology and Drug Discovery 204795 CH 31 Section des sciences pharmaceutiques 17 false 1362 Modélisation biomoléculaire et pharmaceutique The Journal of chemical physics 163 16 ab49ee04-f9ec-49ca-bf44-97403cc76c30 Article (Published version) Public 164111_1_5.0287856.pdf 8154138 application/pdf CC BY-NC-ND-4.0 a411f8ad490a92489876562bdc1f80c3bf7112717080abe797779ef6d3032318 openAccess Faculté des sciences / Section des sciences pharmaceutiques

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All you need is water: Converging ligand binding simulations with hydration collective variables	The Journal of chemical physics			2025	1	0

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