We investigated the binding properties of the metalloprotease inhibitors hydroxamate, methanethiolate, and methylphosphoramidate to a model coordination site occurring in several Zn2؉ metalloproteases, including thermolysin. This was carried out using both the SIBFA (sum of interactions between fragments ab initio-computed) molecular mechanics and the SCF/MP2 procedures for the purpose of evaluating SIBFA as a metalloenzyme modeling tool. The energyminimized structures were closely similar to the X-ray crystallographic structures of related thermolysin-inhibitor complexes. We found that selectivity between alternative geometries and between inhibitors usually stemmed from multiple interaction components included in SIBFA. The binding strength sequence is hydroxamate G methanethiolate H methylphosphoramidate from multiple interaction components included in SIBFA. The trends in interaction energy components, rankings, and preferences for mono-or bidentate binding were consistent in both computational procedures. We also compared the Zn2؉ vs. Mg2؉ selectivities in several other polycoordinated sites having various ''hard'' and ''soft'' qualities. This included a hexahydrate, a model representing Mg2؉/Ca2؉ binding sites, a chlorophyll-like structure, and a zinc finger model. The latter three favor Zn2؉ over Mg2؉ by a greater degree than the hydrated state, but the selectivity varies widely according to the ligand ''softness.'' SIBFA was able to match the ab initio binding energies by F2%, with the SIBFA terms representing dispersion and charge-transfer contributing the most to Zn2؉/ Mg2؉ selectivity. These results showed this procedure to be a very capable modeling tool for metalloenzyme problems, in this case giving valuable information about details and limitations of ''hard'' and ''soft'' selectivity trends.