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 bein g able to calculate free energies in the solution phase, has been show n in recent times to have various shortcomings. For chemical systems t he major problems are faced when studying a conformationally flexible and/or charged molecule due to the large phase space and long-range fo rces involved. In this paper we take as a model the well-studied syste m of histamine monocation in aqueous solution and calculate the tautom erism equilibrium constant. The solution-phase free energy difference between the tautomers is split into intra- and intermolecular parts, a nd these contributions are calculated separately, the former with ab i nitio methods, the latter with a molecular mechanics potential. This a llows the performance of different parts of the calculation to be exam ined. It is found that a result in good agreement with experiment is o btained if various points are noted. In order to get convergence betwe en independent runs, it was necessary to run over 2 ps of equilibratio n between windows to ensure solvent relaxation and 8 ps of data collec tion in each window. This is much longer than the protocol used in ear lier calculations. The result is also significantly altered by the use of different atom point charges, and it was found necessary to take i nto account the conformational species seen during the simulation in t he charge set used. Finally, an implementation of the image charge rea ction field of Friedman was used to model the long-range part of the C oulombic forces, which is seen to affect the result by around 4 kJ mol -1.