QUANTUM-CHEMICAL ANALYSIS OF THE PROTEOLYTIC ENZYMES ACTION MECHANISM. IV. THE HYDROLYSIS OF AMIDES BY ASPARTYL PROTEASES

S. L. ALEXANDROV, V. K. ANTONOV

M. M. Shemyakin Institute of Bioorganic Chemistry, Academy of Sciences of the USSR, Moscow

Abstract: The model systems of amide hydrolysis in the presence of two acetic acid molecules (modelling the Asp-33 and Asp-213 residues) with the former molecule ionized was ana* lysed by the CNDO/2 method. Polarization of the C=O bond in N-methylacetamide (modelling a substrate) and, moreover, protonation of the carbonyl O-atom were found to be practically impossible for all permissible positions of the Asp-213 Hδl-proton. The efficiency of the nucleophilic attack proceeding via general base mechanism was shown to be due to the increased negative charge on the reacting 0-atom of a water molecule, whose one of the protons is hydrogen-bonded with one of the acetate anion's O-atoms. The proton transfer on the amide N-atom of the substrate's leaving group is also realized by acetic acid (Asp-213), which, at a certain substrate orientation, is the proton donor after synchronous rotation of both carboxyl groups of the reacting acids on 180░ around CβŚCγ bond. Efficiency and specificity of the amide hydrolysis are suggested to depend on the orientation of the water molecule with regard to the Asp-33 0-atom (the hydrogen bond length determining the excess of the negative charge on the water molecule's O-atom), and of the substrate (especially, its peptide bond) with regard to the plane of the conjugated O-atoms of two acetic acid molecules.

Russian Journal of Bioorganic Chemistry 1990, 16 (4):464-475

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