Modest protein-crowder attractive interactions can counteract enhancement of protein association by intermolecular excluded volume interactions.
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We study the effects of attractive interactions between spherical crowders and protein residues on the thermodynamics and structure of two weakly binding protein complexes: ubiquitin/UIM1 and cytochrome c/cytochrome c peroxidase. Systematic replica exchange Monte Carlo (REMC) simulations are performed over a range of attraction strengths and crowder packing fractions using a transferable coarse-grained protein binding model. We find that moderate attractive interactions (0.2 kcal/mol) between crowders and protein residues can destabilize protein association, and therefore counteract the stabilizing effect of excluded volume interactions. The destabilization of protein binding, as measured by an increase in binding free energy, increases with increasing crowder packing fraction. For a critical attraction strength value, which is found to be approximately independent of crowder packing fraction, the destabilization due to attractions is exactly canceled by the stabilization effect of excluded volume interactions. This results in a net zero change in binding free energy with respect to a crowder-free solution. Further, we find that attractive interactions between crowders and protein residues can favor transiently bound encounter complexes over the native specific complexes in the bound state. We propose a simple theoretical model based on the scaled particle theory augmented by a mean-field attraction term that can explain our simulation results semiquantitatively.
