Modulation of the affinity of aspartic proteases by the mutated residues in active site models.

The active sites of 3 types of aspartic proteases are modeled, based on crystallographic coordinates of endothiapepsin and of a model of HIV-1 protease. The enthalpies of deprotonation from neutral to mono-anion and to dianion are calculated with semiempirical minimal neglect of differential overlap, hydrogen bonding corrected (MNDO/H). This quantum mechanical study of models for the active sites of pepsins, human renin and retroviral aspartic proteases demonstrates that the replacements of Thr-218 from pepsins by Ala in human renin and of both Ser-35 and Thr-218 by alanines in retroviral proteases increases the proton affinity and modulates the charge distribution of those active sites compared to the pepsins.