Calculations of relative hydration free energies: A comparative study using thermodynamic integration and an extrapolation method based on a single reference state

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 cons ists in first generating one single long trajectory using an unphysical ref erence state and in using afterward this trajectory for the estimation of t he 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) wa s used to calculate by extrapolation the free energy changes for the mutati ons of pyrogallol, catechol, and phenol to benzene in water and in vacuo. T he 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 in vestigate the limitations of the method. The influence of various simulatio n parameters (choice of the unphysical reference state, simulation length. soft-core scaling parameter cr) on the final free energy values was examine d. Benzene derivatives with hydroxyalkyl and/or bulky functional groups of increasing sizes were mutated into benzene. The results for simulations bot h in water and in vacuo were compared to the free energy results obtained b y thermodynamic integration and to the experimental values of similar molec ules, The results showed that for small mutations (deletion of functional g roups with up to three atoms) the extrapolation method is reliable. However . the free energies calculated for the deletion of larger functional groups showed different accuracy levels depending on the chosen simulation parame ters. For the largest mutations the thc thermodynamic integration method al so showed convergence problems. This study therefore demonstrated the usefu lness of the extrapolation method for molecules of similar size, but showed the difficulties of obtaining reliable results for molecules that substant ially differ from each other.