Mechanism of Action of Aspartic Proteases

Abstract

Analysis of crystallographic structures of aspartic proteases allows to conclude that nonbonded interactions of various enzymes of this family with respective specific substrates produce in every case practically identical unstable electronic systems which include catalytic groups of the active center, a cleaved peptide bond and a water molecule. The idea of a similar mutual orientation of these components in all nonbonded complexes of aspartic proteases [1] can reliably be verified by an a priori semi-empirical computation of the enzyme-substrate interactions for two representatives of this group which differ essentially in their amino acid sequences and three-dimensional structures. As the objects of theoretical investigations of catalytic mechanism of aspartic proteases, we have chosen human immunodeficiency virus protease (HIV 1-PR) and fungal protease rhizopuspepsin. Because of the restricted volume of the publication, here we only present the results for rhizopuspepsin and its interaction with the substrate Ac—Pro¹—Phe²—His³—Lys⁴—Phe⁵—Val⁶—OMe and the substrate-like inhibitor Ac—Pro¹—Phe²—His³—Phe⁴(Ψ)—CH₂—Phe⁵—Val⁶—OMe which forms a stable complex, investigated by X-ray diffraction [2]. The results for the HIV 1-PR are to be published in a separate communication. A quantitative study of the rhizopuspepsin catalytic act is based on the theory and computation method described recently [3]. According to this scheme, the conformational properties of free molecules of the substrate, inhibitor and of the enzyme active center were analyzed first, and then a formation of the enzyme-inhibitor and enzyme-substrate complex was modeled.