Quantum mechanical/molecular mechanical study of anthrax lethal factor catalysis

We report a hybrid quantum mechanical and molecular mechanical study of the catalysis of anthrax lethal factor. The calculations suggest that the zinc peptidase uses the same general base-general acid mechanism as in thermolysin and carboxypeptidase A, in which a zinc-bound water is activated by Glu...

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Bibliographic Details
Published in:Theoretical chemistry accounts 2011, Vol.128 (1), p.83-90
Main Authors: Smith, Christopher R., Smith, Gregory K., Yang, Zhenxiao, Xu, Dingguo, Guo, Hua
Format: Article
Language:English
Subjects:
Atomic/Molecular Structure and Spectra
Chemistry
Chemistry and Materials Science
Inorganic Chemistry
Organic Chemistry
Physical Chemistry
Regular Article
Theoretical and Computational Chemistry
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Summary:We report a hybrid quantum mechanical and molecular mechanical study of the catalysis of anthrax lethal factor. The calculations suggest that the zinc peptidase uses the same general base-general acid mechanism as in thermolysin and carboxypeptidase A, in which a zinc-bound water is activated by Glu687 to nucleophilically attack the scissile carbonyl carbon in the substrate. The catalysis is aided by an oxyanion hole formed by the zinc ion and the side chain of Tyr728, which provide stabilization for the fractionally charged carbonyl oxygen. The assigned role of Tyr728 differs from previous suggestions but is consistent with the established mechanism of other zinc proteases.
ISSN:1432-881X
1432-2234
DOI:10.1007/s00214-010-0765-z