Optimizing solute-water van der Waals interactions to reproduce solvation free energies

J Phys Chem B. 2012 Apr 19;116(15):4524-34. doi: 10.1021/jp2118373. Epub 2012 Apr 6.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Dipeptides / chemistry*
  • Hydrophobic and Hydrophilic Interactions*
  • Protein Folding*
  • Solubility
  • Solutions
  • Thermodynamics*
  • Water / chemistry*


  • Dipeptides
  • Solutions
  • Water