Balanced protein-water interactions improve properties of disordered proteins and non-specific protein association

Robert B. Best, Wenwei Zheng, Jeetain Mittal

Research output: Contribution to journalArticle

248 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)5113-5124
Number of pages12
JournalJournal of Chemical Theory and Computation
Volume10
Issue number11
DOIs
StatePublished - Nov 11 2014

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ASJC Scopus subject areas

  • Computer Science Applications
  • Physical and Theoretical Chemistry

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