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. 2009 Feb 10;5(2):350-358.
doi: 10.1021/ct800409d.

Small molecule hydration free energies in explicit solvent: An extensive test of fixed-charge atomistic simulations

David L Mobley  1 , Christopher I Bayly, Matthew D Cooper, Michael R Shirts, Ken A Dill
Affiliations

Small molecule hydration free energies in explicit solvent: An extensive test of fixed-charge atomistic simulations

David L Mobley et al. J Chem Theory Comput. .

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 non-polar 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 non-polar part both scale roughly with surface area (or volume) of the solute, the total non-polar 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 future development of force fields and solvation models.

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Figures

FIG. 1
FIG. 1. Calculated hydration free energies versus experiment
Shown are the calculated hydration free energies versus experiment for the full test set. The diagonal line is x = y. Vertical error bars denote computed uncertainties, and horizontal error bars are a conservative estimate.
FIG. 2
FIG. 2. CDFs for selected functional groups versus error
Shown are cumulative distribution functions for finding compounds with particular functional groups at a given ranked error. Compounds found far to the left have very large errors; compounds far to the right have very small errors. An ideal random distribution of errors would give rise to a linear rise in the CDF, as shown by the dotted line. CDFs are shown for (a) alkynes before fixing the Lennard-Jones well-depth; (b) alkynes after fixing the Lennard-Jones well-depth, and (c) aromatics.
FIG. 3
FIG. 3. Nonpolar components versus solvent accessible surface area and volume
Shown are the calculated nonpolar component of the hydration free energies versus solvent accessible surface area and volume for the compounds in the set. Carbon and hydrogen containing compounds are black, those with oxygen additionally are red, those with nitrogen additionally are blue, and those with nitrogen and oxygen both are magenta. Compounds with diamond symbols contain other elements in addition to C, H, N, and O. In the surface area plot, the line is a typical implicit solvent nonpolar component estimate of Gnp = (0.00542· SA + 0.92) kcal/mol.
FIG. 4
FIG. 4. Repulsive and attractive parts of the nonpolar component versus surface area
Shown are the repulsive (a) and attractive (b) parts of the nonpolar component, as calculated using the WCA separation, plotted versus the solvent accessible surface area for solutes in the test set. Similar plots comparing the repulsive and attractive components to volume are given in the Supporting Information.
See this image and copyright information in PMC

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