Balanced Protein-Water Interactions Improve Properties of Disordered Proteins and Non-Specific Protein Association

Some frequently encountered deficiencies in all-atom molecular simulations, such as nonspecific proteinprotein interactions being too strong, and unfolded or disordered states being too collapsed, suggest that proteins are insufficiently well solvated in simulations using current state-of-the-art force fields. To address these issues, we make the simplest possible change, by modifying the short-range proteinwater pair interactions, and leaving all the waterwater and proteinprotein parameters unchanged. We find that a modest strengthening of proteinwater interactions is sufficient to recover the correct dimensions of intrinsically disordered or unfolded proteins, as determined by direct comparison with small-angle X-ray scattering (SAXS) and Forster resonance energy transfer (FRET) data. The modification also results in more realistic protein-protein affinities, and average solvation free energies of model compounds which are more consistent with experiment. Most importantly, we show that this scaling is small enough not to affect adversely the stability of the folded state, with only a modest effect on the stability of model peptides forming a-helix and Beta-sheet structures. The proposed adjustment opens the way to more accurate atomistic simulations of proteins, particularly for intrinsically disordered proteins, proteinprotein association, and crowded cellular environments.