Origin of enthalpic depletion forces

Solutes excluded from macromolecules or colloids are known to drive depletion attractions. The established Asakura-Oosawa model, as well as subsequent theories aimed at explaining the effects of macromolecular crowding, attribute depletion forces to diminished hard-core excluded volume upon compaction, and hence predict depletion forces dominated by entropy. However, recent experiments measuring the effect of preferentially excluded solutes on protein folding and macromolecular association find these forces can also be enthalpic. We use simulations of macromolecular association in explicit binary cosolute-solvent mixtures, with solvent and cosolute intermolecular interactions that go beyond hard-cores, to show that not all cosolutes conform to the established entropically dominated model. We further demonstrate how the enthalpically dominated depletion forces that we find can be well described within an Asakura-Oosawa like model provided that the hard-core macromolecule-cosolute potential of mean force is augmented by a "soft" step-like repulsion.