For SAM, in contrast to CAT and Mg 2+ , the VDD charge sensitivity is initially increasing until a QM region size of about 300 atoms is reached (region 4), before the sensitivity starts to slightly decrease when further enlarging the QM region. This different behavior arises because SAM is a much larger molecule than CAT and thus offers numerous possibilities for charge redistribution and more contact sites to adjacent residues. For the small QM regions, the possibilities of charge redistribution to adjacent QM residues are reduced, which results in a smaller VDD charge sensitivity in these cases. In region 4, five residues (GLY65, TYR67, TYR70, SER71 and ILE90) which are part of the SAM coordination sphere are added to the QM region. This enables a wide variability for the SAM charge to be redistributed, resulting in an increase in sensitivity for this QM model. In larger QM regions, the SAM charge sensitivity is then gradually decreasing because only single residues being part of the SAM coordination sphere are added, such as MET39 in region 5 or TRP142 in region 6.