Small Molecule Hydration Free Energies in Explicit Solvent: An Extensive Test of Fixed-Charge Atomistic Simulations

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Abstract
Using molecular dynamics free energy simulations with TIP3P explicit solvent, we compute the hydration free energies of 504 neutral small organic molecules and compare them to experiments. We find, first, good general agreement between the simulations and the experiments, with an rms error of 1.24 kcal/mol over the whole set (i.e., about 2 kT) and a correlation coefficient of 0.89. Second, we use an automated procedure to identify systematic errors for some classes of compounds and suggest some improvements to the force field. We find that alkyne hydration free energies are particularly poorly predicted due to problems with a Lennard-Jones well depth and find that an alternate choice for this well depth largely rectifies the situation. Third, we study the nonpolar component of hydration free energies—that is, the part that is not due to electrostatics. While we find that repulsive and attractive components of the nonpolar part both scale roughly with surface area (or volume) of the solute, the total nonpolar free energy does not scale with the solute surface area or volume, because it is a small difference between large components and is dominated by the deviations from the trend. While the methods used here are not new, this is a more extensive test than previous explicit solvent studies, and the size of the test set allows identification of systematic problems with force field parameters for particular classes of compounds. We believe that the computed free energies and components will be valuable to others in the future development of force fields and solvation models.

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