title: Optimizing solute-water van der Waals interactions to reproduce solvation free energies.
abstract: An accurate representation of solute-water interactions is necessary for molecular dynamics simulations of biomolecules that reside in aqueous environments. Modern force fields and advanced water models describe solute-solute and water-water interactions reasonably accurately but have known shortcomings in describing solute-water interactions, demonstrated by the large differences between calculated and experimental solvation free energies across a range of peptide and drug chemistries. In this work, we introduce a method for optimizing solute-water van der Waals interactions to reproduce experimental solvation free energy data and apply it to the optimization of a fixed charge force field (AMBER ff99SB/GAFF) and advanced water model (TIP4P-Ew). We show that, with these optimizations, the combination of AMBER ff99SB/GAFF and TIP4P-Ew is able to reproduce the solvation free energies of a variety of biologically relevant small molecules to within 1.0 k(B)T. We further validate these optimizations by examining the aggregation propensities of dipeptide-water solutions, the conformational preferences of short disordered peptides, and the native state stability and dynamics of a folded protein.
authors.affiliation: California Institute of Quantitative Biosciences, University of California, Berkeley, Berkeley, California 94720-3220, United States.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Nerenberg
authors.forename: Brian
authors.initials: B
authors.lastname: Jo
authors.forename: Clare
authors.initials: C
authors.lastname: So
authors.forename: Ajay
authors.initials: A
authors.lastname: Tripathy
authors.forename: Teresa
authors.initials: T
authors.lastname: Head-Gordon
mesh_terms: D004151:Dipeptides / Q000737:chemistry*; D057927:Hydrophobic and Hydrophilic Interactions; D017510:Protein Folding; D012995:Solubility; D012996:Solutions; D013816:Thermodynamics; D014867:Water / Q000737:chemistry*
chemical_list: D004151:Dipeptides; D012996:Solutions; D014867:Water