title: Modeling of inhibitor-metalloenzyme interactions and selectivity using molecular mechanics grounded in quantum chemistry.
abstract: 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 > or = 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.
authors.affiliation: Department of Physiology and Biophysics, Mount Sinai School of Medicine, New York, New York, USA.
authors.forename: D R
authors.initials: DR
authors.lastname: Garmer
authors.forename: N
authors.initials: N
authors.lastname: Gresh
authors.forename: B P
authors.initials: BP
authors.lastname: Roques
mesh_terms: D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006877:Hydroxamic Acids / Q000737:chemistry / Q000378:metabolism; D008433:Mathematics; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D008670:Metals / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000378:metabolism; D011480:Protease Inhibitors / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D013438:Sulfhydryl Compounds / Q000737:chemistry / Q000378:metabolism; D013816:Thermodynamics; D013820:Thermolysin / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D015032:Zinc / Q000737:chemistry / Q000378:metabolism
chemical_list: D006877:Hydroxamic Acids; D008670:Metals; D009943:Organophosphorus Compounds; D011480:Protease Inhibitors; D013438:Sulfhydryl Compounds; C112626:methyl phosphoamidate; C005231:methylmercaptan; D008666:Metalloendopeptidases; D013820:Thermolysin; D015032:Zinc