Given a two-or three-body approximation for a large enzyme model possessing charged side chains, one might worry about neglect of long-range interactions. We address this by assessing a multilayer fragmentation scheme in which a low-level calculation on the entire system is used to correct for errors introduced by fragmentation, while the subsystems are described at a higher level of theory. This strategy has been suggested by others under various names, and is illustrated in Fig. by analogy to the "ONIOM" approach for QM/ MM calculations. Both the subsystems and the supersystem are computed at the lower level of theory and the difference between low-level supersystem and lowlevel MBE(n) calculations provides a correction for the effects of fragmentation, including the possible neglect of long-range polarization. Raghavachari and co-workers have made extensive use of this idea for calculations in proteins, and our two-layer procedure is equivalent to the "MIM2" strategy defined in Ref. 85.