Free energy calculations from one-step perturbations.

The one-step perturbation approach offers an efficient means to estimate free energy differences. It may be applied to estimate solvation free energies, conformational preferences or relative free energies of binding of series of compounds to a common receptor. Applicability of the method depends on the possibility to define a proper reference state which may in itself be an unphysical molecule. Here, we describe practical considerations and explicit guidelines to define a proper reference state, and to efficiently calculate relative free energies. The strengths and limitations of the method are highlighted and special considerations are noted. The method may be applied using many different simulation programs. Here, analyses are exemplified at the hand of the GROMOS simulation package.