The original Asakura–Oosawa model considered only hard-core interactions. In such an athermal mixture the origin of depletion forces is necessarily entropic. If the intermolecular potentials also include repulsive and/or attractive terms, and if the solvent is considered explicitly, the depletion interaction can have additional thermodynamic contributions.
The notion that depletion forces can also be enthalpically driven has surfaced due to recent experiments regarding protein stabilization induced by compatible osmolytes, such as trehalose, glycerol, and sorbitol. These osmolytes are preferentially excluded from protein surfaces, forming a layer of preferential hydration around the proteins. When the protein folds - this exclusion volume diminishes, making the folded state lower in free energy. Hence the excluded osmolytes shift the folding equilibrium towards the folded state. This effect was generally thought to be an entropic force, in the spirit of the original Asakura–Oosawa model and of macromolecular crowding. However, thermodynamic breakdown of the free-energy gain due to osmolyte addition showed the effect is in fact enthalpically driven, whereas entropy can even be disfavorable.
For many cases, the molecular origin of this enthalpically driven depletion force can be traced to an effective "soft" repulsion in the potential of mean force between macromolecule and cosolute. Both Monte-Carlo simulations and a simple analytic model demonstrate that when the hard-core potential (as in Asakura and Oosawa's model) is supplemented with an additional repulsive "softer" interaction, the depletion force can become enthalpically dominated.