Because we allow the amino acids to inhabit their native protonation states, leading to ionic side chains in some cases, there may be concern about long-range polarization interactions. The Zn 2+ ion that is present in two of the LIDS proteins leads to especially large three-and four-body terms as discussed in Section 3 .2. Fragme∩t has the ability to add a low-level, ONIOMstyle supersystem correction for long-range polarization, with the subsystem MBE(n) calculations described at a higher level of theory. Elsewhere, this procedure has been called a two-layer "molecules-in-molecules" approach (MIM2), and it has been used by others under various names. Applying this correction, the total energy for any given calculation, meaning any of the three terms in eq. 6, is