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.
Goldblum
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Department of Pharmaceutical Chemistry, School of Pharmacy, Hebrew University of Jerusalem, Israel.
D000595:Amino Acid Sequence; D016282:Aspartic Acid Endopeptidases; D001665:Binding Sites; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D015684:Gene Products, pol / Q000235:genetics / Q000378:metabolism*; D016333:HIV Protease; D015497:HIV-1 / Q000201:enzymology*; D006801:Humans; D006860:Hydrogen Bonding; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009154:Mutation; D010434:Pepsin A; D012083:Renin; D013816:Thermodynamics
D015684:Gene Products, pol; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C042466:Endothia aspartic proteinase; D016333:HIV Protease; D010434:Pepsin A; D012083:Renin