  As a common view the hydrophobic association between molecular-scale binding
partners is supposed to be dominantly driven by entropy. Recent calorimetric
experiments and computer simulations heavily challenge this established
paradigm by reporting that water's thermodynamic signature in the binding of
small hydrophobic ligands to similar-sized apolar pockets is enthalpy-driven.
Here we show with purely geometric considerations that this controversy can be
resolved if the antagonistic effects of concave and convex bending on water
interface thermodynamics are properly taken into account. A key prediction of
this continuum view is that for fully complementary binding of the convex
ligand to the concave counterpart, water shows a thermodynamic signature very
similar to planar (large-scale) hydrophobic association, that is,
enthalpy-dominated, and hardly depends on the particular pocket/ligand
geometry. A detailed comparison to recent simulation data qualitatively
supports the validity of our perspective down to subnanometer scales. Our
findings have important implications for the interpretation of thermodynamic
signatures found in molecular recognition and association processes.
Furthermore, traditional implicit solvent models may benefit from our view with
respect to their ability to predict binding free energies and entropies.
