Histograms of all three-body interactions 1ZP5 (Fig. ) exhibit a few significant outliers where |∆E IJK | 0.01 E h . The largest of these three-body contributions is about 30 kcal/mol. The metalloenzyme 1MMQ has one very large three-body interaction of 23 kcal/mol (Fig. ), whereas for 1O48 and 1BOZ the three-body corrections are much smaller (Figs. and). Inspecting the fragments that give rise to the outliers in 1ZP5 and 1MMQ confirms that each contains the Zn 2+ cation, the ligand, and a residue whose side chain is coordinated to the ligand. For example, the large three body term for 1MMQ contains GLU121, which is coordinated to the carboxylic acid group in the binding site. While it is not surprising that a divalent cation engenders significant nonadditive polarization, these results underscore the fact that MBE(2) is not always a good approximation for protein-ligand interaction energies.