Calculation of the tautomer ratio of histamine in aqueous solution using free energy perturbation methods : an in-depth study

The free energy perturbation (FEP) method, despite the promise of being able to calculate free energiw in the solution phase, has been shown in recent times to have various shortcomings. For chemical systems the major problems are faced when studying a conformationally flexible and/or charged molecule due to the large phase space and long-range forces involved. In this paper we take as a model the well-studied system of histamine monocation in aqueous solution and calculate the tautomerism equilibrium constant. The solution-phase free energy difference between the tautomers is split into intra- and intermolecular parts, and these contributions are calculated separately, the former with ab initio methods, the latter with a molecular mechanics potential