Free energies of hydration using restrained electrostatic potential derived charges via free energy perturbations and linear response

To determine the reliability of the restrained electrostatic potential derived (REPD) charge method described in a companion article, the free energies of hydration of 22 simple organic molecules were calculated using free energy perturbations and linear response theory. Of the four charge sets examined using the free energy perturbation method, REPD/6-31(+)G* charges gave the closest agreement with the experiment, followed by conventional EPD charges derived at the 6-31G* level. The average absolute error for the former was 2.9 kJ mol(-1) and for the latter was 3.5 kJ mol(-1). The linear response method was then used to predict free energies of hydration based on the average van der Waals and electrostatic solute-solvent energies obtained from Monte Carlo computer simulations and solvent accessible surface areas. Use of the three parameter relationship gave a good agreement with the experiment. However, a number of simpler fitting functions were also examined and found to be only marginally less reliable. A careful statistical analysis of the linear response method is therefore needed. (C) 1999 John Wiley & Sons, Inc.