Optimizing Solute–Water van der Waals Interactions To Reproduce Solvation Free Energies

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 kBT. 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.