How interface geometry dictates water's thermodynamic signature in hydrophobic association

TL;DR

This paper demonstrates that water's thermodynamic signature in hydrophobic association is dictated by interface geometry, resolving conflicting experimental and simulation results by considering concave and convex effects.

Contribution

It introduces a geometric continuum model that explains the thermodynamic signatures of water in hydrophobic binding, unifying previous conflicting observations.

Findings

Water shows enthalpy-driven signatures in convex-concave binding.

Interface geometry determines the thermodynamic signature of water.

Model qualitatively matches recent simulation data at subnanometer scales.

Abstract

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.