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

TLDR

All‑atom simulations often over‑strengthen nonspecific protein–protein interactions and collapse unfolded states, indicating insufficient protein solvation in current force fields. The authors aim to correct these deficiencies by adjusting short‑range protein–water pair interactions. They modify only the protein–water interaction parameters, leaving water–water and protein–protein terms unchanged. A modest strengthening of protein–water interactions restores the correct dimensions of intrinsically disordered proteins, produces realistic protein–protein affinities and solvation free energies, and has only a slight effect on folded‑state stability, thereby enabling more accurate atomistic simulations of disordered proteins and crowded cellular environments.

Abstract

Some frequently encountered deficiencies in all-atom molecular simulations, such as nonspecific protein–protein 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 protein–water pair interactions, and leaving all the water–water and protein–protein parameters unchanged. We find that a modest strengthening of protein–water 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 Förster 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 α-helix and β-sheet structures. The proposed adjustment opens the way to more accurate atomistic simulations of proteins, particularly for intrinsically disordered proteins, protein–protein association, and crowded cellular environments.