Molecular driving forces of the pocket-ligand hydrophobic association

► MD simulations showed that pocket-ligand nonpolar binding is enthalpy-driven. ► The Gibbs energy gain upon hydrophobic association is due to WASA decrease. ► The latter produces a gain in translational entropy of water molecules. ► This is the main driving force of hydrophobic association. ► Water reorganisation is characterised by total enthalpy-entropy compensation.