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Modeling of inhibitor–metalloenzyme interactions and selectivity using molecular mechanics grounded in quantum chemistry
Author(s) -
Garmer David R.,
Gresh Nohad,
Roques BernardPierre
Publication year - 1998
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/(sici)1097-0134(19980401)31:1<42::aid-prot5>3.0.co;2-j
Subject(s) - thermolysin , chemistry , ab initio , selectivity , interaction energy , binding energy , computational chemistry , fragment molecular orbital , molecular model , ligand (biochemistry) , stereochemistry , molecular orbital , molecule , organic chemistry , catalysis , enzyme , physics , trypsin , nuclear physics , biochemistry , receptor
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 energy‐minimized 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 > methanethiolate ≥ 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 <2%, 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. Proteins 31:42–60, 1998. © 1998 Wiley‐Liss, Inc.