We use explicit solvent molecular dynamics simulations to estimate free energy, enthalpy, and entropy changes along the cavity−ligand association coordinate for a set of seven model systems with varying physicochemical properties. Owing to the simplicity of the considered systems we can directly investigate the role of water thermodynamics in molecular recognition. A broad range of thermodynamic signatures is found in which water (rather than cavity or ligand) enthalpic or entropic contributions appear to drive cavity−ligand binding or rejection. The unprecedented, nanoscale picture of hydration thermodynamics can help the interpretation and design of protein−ligand binding experiments. Our study opens appealing perspectives to tackle the challenge of solvent entropy estimation in complex systems and for improving molecular simulation models.

Hydrophobic association is often recognized as being driven by favorable entropic contributions. Here, using explicit solvent molecular dynamics simulations we investigate binding in a model hydrophobic receptor−ligand system which appears, instead, to be driven by enthalpy and opposed by entropy. We use the temperature dependence of the potential of mean force to analyze the thermodynamic contributions along the association coordinate. Relating such contributions to the ongoing changes in system hydration allows us to demonstrate that the overall binding thermodynamics is determined by the expulsion of disorganized water from the receptor cavity. Our model study sheds light on the solvent-induced driving forces for receptor−ligand association of general, transferable relevance for biological systems with poorly hydrated binding sites.