Approaches for calculating solvation free energies and enthalpies demonstrated with an update of the FreeSolv database

Abstract

Solvation free energies can now be calculated precisely from molecular simulations, providing a valuable test of the energy functions underlying these simulations. Here, we briefly review "alchemical" approaches for calculating the solvation free energies of small, neutral organic molecules from molecular simulations, and illustrate by applying them to calculate aqueous solvation free energies (hydration free energies). These approaches use a non-physical pathway to compute free energy differences from a simulation or set of simulations and appear to be a particularly robust and general-purpose approach for this task. We also present an update (version 0.5) to our FreeSolv database of experimental and calculated hydration free energies of neutral compounds and provide input files in formats for several simulation packages. This revision to FreeSolv provides calculated values generated with a single protocol and software version, rather than the heterogeneous protocols used in the prior version of the database. We also further update the database to provide calculated enthalpies and entropies of hydration and some experimental enthalpies and entropies, as well as electrostatic and nonpolar components of solvation free energies.

Figure 1

Thermodynamic cycle used to calculate hydration free energies (or, more generally, solvation free energies). In (A), we have states in which charge-charge interactions between the solute and its environment are progressively turned off. In (B) dispersion interactions between solute and water are progressively turned off. Colored atoms (green for carbon, red for oxygen, white for hydrogen) have electrostatic and nonpolar interactions with the environment; gray atoms retain only nonpolar interactions; and transparent atoms have no interactions with their environment (and thus represent the solute in vacuum).

Figure 2

Calculated versus experimental hydration free energies for the compounds in Free-Solv version 0.5. Calculated values are on the vertical axis and experimental on the horizontal.

Figure 3

Conformational enthalpies and associated entropies of compounds with highest $\mathrm{\Delta }{H}_{\mathit{conf}}^{\mathit{hyd}}$. Error bars represent the standard error.