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 <i>k</i>_B<i>T</i>. 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