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American Chemical Society, Journal of Physical Chemistry B (Soft Condensed Matter and Biophysical Chemistry), 15(116), p. 4524-4534, 2012

DOI: 10.1021/jp2118373

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

Journal article published in 2012 by Paul S. Nerenberg, Brian Jo ORCID, Clare So, Ajay Tripathy, Teresa Head-Gordon
This paper is available in a repository.
This paper is available in a repository.

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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.