Calculations of Relative Hydration Free Energies: A Comparative Study Using Thermodynamic Integration and an Extrapolation Method Based on a Single Reference State

Abstract

The relative hydration free energies of a series of organic molecules were calculated from molecular dynamics (MD) simulations using an extrapolation method in combination with soft-core potential scaling. This technique consists in first generating one single long trajectory using an unphysical reference state and in using afterward this trajectory for the estimation of the free energy difference between several molecules. First, we investigated the accuracy of the method for the deletion of small functional groups. A trajectory from an MD simulation of pyrogallol (1,2,3-trihydroxybenzene) was used to calculate by extrapolation the free energy changes for the mutations of pyrogallol, catechol, and phenol to benzene in water and in vacuo. The results were compared to those obtained by thermodynamic integration, to experimental data, and to values calculated using a semiempirical method. In a second step, increasingly larger mutations were studied in order to investigate the limitations of the method. The ...