Thus, 1BOZ appears to be a case where cumulative errors from a enormous number of subsystem calculations skews the result, a possibility that we have noted previously. A histogram of four-body terms for 1BOZ with 12 Å cutoff can be found in Fig. . Energetically, these terms are two orders of magnitude smaller than the three-body terms (shown in Fig. ), but considerably more numerous. Incorporation of bottom-up energy-based screening 26 into our enzymatic fragmentation protocol will be essential for routine application of MBE(4) to model systems of this size.