Quantum mechanical/molecular mechanical study of anthrax lethal factor catalysis

Abstract

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.