For the Cytochrome C system, we performed QM/MM calculations using Py-Chemshell 50,51 with TURBOMOLE . We defined the QM region as the Fe-containing heme, axial ligand, and the Cys residues ligated to the heme propionate. The QM region was treated with unrestricted DFT, using the B3-LYP D3-BJ functional, with def2-TZVP basis set for Fe and def2-SVP for all other atoms for optimizations. For single-point energy calculations, we used the def2-TZVP basis set for all atoms in the QM region. The MM region was defined as 8Å beyond the QM region, and was treated with the AMBER force field. All atoms past the MM region were frozen, and both the MM