The free energy perturbation (FEP) method, despite the promise of being able to calculate free energies 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. This allows the performance of different parts of the calculation to be examined. It is found that a result in good agreement with experiment is obtained if various points are noted. In order to get convergence between independent runs, it was necessary to run over 2 ps of equilibration between windows to ensure solvent relaxation and 8 ps of data collection in each window. This is much longer than the protocol used in earlier calculations. The result is also significantly altered by the use of different atom point charges, and it was found necessary to take into account the conformational species seen during the simulation in the charge set used. Finally, an implementation of the image charge reaction field of Friedman was used to model the long-range part of the Coulombic forces, which is seen to affect the result by around 4 kJ mol-1.