Improving the study of proton transfers between amino acid side chains in solution: choosing appropriate DFT functionals and avoiding hidden pitfalls
We have studied the influence of implicit solvent models, inclusion of explicit water molecules, inclusion of vibrational effects, and density functionals on the quality of the predicted pK a of small amino acid sidechain models. We found that the inclusion of vibrational effects and explicit water molecules is crucial to improve the correlation between the computed and the experimental values. However, achieving convergence of the results requires the addition of too many explicit water
... plicit water molecules, which generate new problems related to the presence of multiple minima in the potential energy surface. It thus appears that a satisfactory ab initio prediction of amino acid sidechain pK a will require methods that fully sample the potential energy surface in the presence of large solvation shells, while at the same time computing vibrational contributions to the enthalpy and entropy of the system under study in all points of that surface. Pending development of efficient algorithms for those computations, we strongly suggest that whenever abnormal protonation states are found in a computational study the reaction profile should be computed under the each of the different protonation micro-states by constraining the relevant N-H or O-H bonds, in order to avoid artifacts inherent to the complex nature of the factors contributing to the pK a .