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

Abstract

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.