QUANTITATIVE-EVALUATION OF HYDRATION THERMODYNAMICS WITH A CONTINUUM MODEL

We attempt to analyze whether experimental entropies, enthalpies and f ree energies of hydration of small uncharged molecules can be quantita tively rationalized with a continuum model including a classical react ion field formalism. We find that a simple proportionality to accessib le surface with five different atom types allows satisfactory (within 1-1.5 kcal/mol) reproduction of hydration entropies (T Delta S) of ove r 40 solutes. The agreement with experiment can possibly be improved i f proximity effects and configurational contributions to transfer entr opies are taken into account. In calculations of hydration enthalpies a reasonable agreement with experimental data can be obtained only whe n solute polarizability is taken into account. Electrostatic contribut ions to calculated hydration enthalpies exhibit strong dependencies on both the magnitude and the direction of molecular dipole moments. We demonstrate that for 20 molecules with experimentally measured vacuum dipole moments density functional calculations with DZVPD basis set in cluding diffuse functions on d-orbitals allows prediction of experimen tal dipole moments within 0.1 D. At a fixed direction of the molecular dipole moment, mu, the electrostatic component of hydration enthalpy varies as mu(2). Thus an uncertainty of 0.1 D corresponds to uncertain ties of 0.5-0.7 kcal/mol in hydration enthalpies of most small dipolar solutes. A 30 degrees change in the direction of the molecular dipole together with the corresponding change in the quadrupole moment can r esult in a change of hydration enthalpy of 3 kcal/mol. Changes in the quadrupole moment alone can result in hydration enthalpy changes of ov er 1 kcal/mol. Representations of multipole expansions by point charge s on nuclei fitted to molecular electrostatic potentials cannot accura tely reproduce all these factors. Use of such point charges in calcula tions of hydration enthalpies predictably leads to discrepancies with experiment of approximate to 3 kcal/mol for some solutes. However, err ors in hydration enthalpies and hydration entropies are usually compen sating leading in most cases to agreement between calculated and exper imental free energies of hydration within 1.5 kcal/mol.