The QM/MM Hamiltonian, which combines quantum mechanics and molecular mechanics, includes terms for long range electrostatic interactions and can thus model all of the 8,860 atoms in VCPO in comparison to the 126 atom model in Gupta et al.'s study. QM/MM modeling is necessary because it has been found previously that the long range electrostatic interactions substantially influence the protonation state of VCPO, and the effects of the protein environment on the active site model are very important in VCPO. Another advantage of QM/MM modeling of VCPO is that many heavy atoms do not need to be constrained in order to obtain convergence as they do in a QM model.