Mechanism of action of aspartyl proteases. VII. Noncovalent complexes of HIV-1 aspartic protease with substrate and substrate-like inhibitor

A computer model of a noncovalent complex of HIV-1 aspartyl protease with s ubstrate-like inhibitor JG-365 was a priori constructed by using the approa ches of theoretical conformational analysis and molecular mechanics. The ro ot mean square deviation of the calculated conformation of the inhibitor fr om the X-ray diffraction analysis data was 0.87 Angstrom. These results enabled the a priori calculation of the structure of noncoval ent complex of HIV-1 protease with a hexapeptide fragment of its native spe cific substrate Ser-Gln-Asn-Tyr-Pro-Ile-Val. The only possible orientation of the cleavable peptide bond in this and the nucleophilic water molecule r elative to the catalytically active Asp residues of the enzyme (Asp25 and A sp125) was found that provides for the chemical transformation of the subst rate to a tetrahedral intermediate. An action mechanism of enzymes of this class was proposed on the basis of the analysis of calculated distances. We showed that neither steric distortion of the cleavable bond nor the format ion of unfavorable contacts in molecules of the enzymes and their substrate s accompany the optimum orientation of substrate molecules at the active si tes of HIV-1 aspartyl proteases and rhizopuspepsin.