Crowding Induced Entropy-Enthalpy Compensation in Protein Association Equilibria

A statistical mechanical theory is presented to predict the effects of macromolecular crowding on protein association equilibria, accounting for both excluded volume and attractive interactions between proteins and crowding molecules. Predicted binding free energies are in excellent agreement with simulation data over a wide range of crowder sizes and packing fractions. It is shown that attractive interactions between proteins and crowding agents counteract the stabilizing effects of excluded volume interactions. A critical attraction strength, for which there is no net effect of crowding, is approximately independent of the crowder packing fraction.