Computation of hydration free energies of organic solutes with an implicit water model

A new approach for computing hydration free energies ΔGsolv of organic solutes is formulated and parameterized. The method combines a conventional PCM (polarizable continuum model) computation for the electrostatic component ΔGel of ΔGsolv and a specially detailed algorithm for treating the complementary nonelectrostatic contributions (ΔGnel). The novel features include the following: (a) two different cavities are used for treating ΔGel and ΔGnel. For the latter case the cavity is larger and based on thermal atomic radii (i.e., slightly reduced van der Waals radii). (b) The cavitation component of ΔGnel is taken to be proportional to the volume of the large cavity. (c) In the treatment of van der Waals interactions, all solute atoms are counted explicitly. The corresponding interaction energies are computed as integrals over the surface of the larger cavity; they are based on Lennard Jones (LJ) type potentials for individual solute atoms. The weighting coefficients of these LJ terms are considered as fitting parameters. Testing this method on a collection of 278 uncharged organic solutes gave satisfactory results. The average error (RMSD) between calculated and experimental free energy values varies between 0.15 and 0.5 kcal/mol for different classes of solutes. The larger deviations found for the case of oxygen compounds are probably due to a poor approximation of H‐bonding in terms of LJ potentials. For the seven compounds with poorest fit to experiment, the error exceeds 1.5 kcal/mol; these outlier points were not included in the parameterization procedure. Several possible origins of these errors are discussed. © 2006 Wiley Periodicals, Inc. J Comput Chem 27: 552–570, 2006

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