Rhizopus pepsin-pepstatin

The mutation of the hydroxyl group positioned in R-configuration at the C(3) atom of the central statine (rSta) residue of the inhibitor gives rise to AAGbind of -0.51 kcal/mol, which is very close to the experimental value of -0.8 kcal/mol. It may be noted here that the starting configuration of the inhibitor in the enzyme-inhibitor complex is the same as that of pepstatin. The crystal structure of rhizopus pepsin or any other aspartic proteinase... 

B. G. Rao, and U. C. Singh, Studies on the binding of pepstatin and its derivatives to Rhizopus pepsin by quantum methanics, molecular mechanics, and free energy perturbation methods, J. Am. Chem. Soc. 113 6735 (1991). 

K. Suguna, E. A. Padlan, R. Bott, J. Boger, K. D. Parris, and D. R. Davies, Structures of complexes of rhizopus pepsin with pepstatin and other statine-containing inhibitors, Proteins 13 195 (1992). 

Figure 1. Schematic representation of the relationships between proposed catalytic and inhibitory mechanisms. A. Postulated general acid-general base catalyzed mechanism for substrate hydrolysis by an aspartyl protease. The water molecule indicated is extensively hydrogen bonded to both aspartic acid residues plus other sites in the active site (see Reference 16 for details). Hydrogen bonds to water are omitted here. B. Kinetic events associated with the inhibition of pepsin by pepstatin. The pro-S hydroxyl group of statine displaces the enzyme immobilized water molecule shown in Figure lA. Variable aspartyl sequence numbers refer to penicillopepsin (pepsin, Rhizopus pepsin), respectively.

B. G. Rao and U. C. Singh, /. Am. Ghem. Soc., 113, 6735 (1991). Studies on the Binding of Pepstatin and Its Derivatives to Rhizopus Pepsin by Quantum Mechanics, Molecular Mechanics and Free Energy Perturbation. 

In an FEP study, Rao and Singh used AMBER 3.3 to determine the relative binding free enei of pepstatin and its derivatives to Rhizopus pepsin. A united-atom and an all-atom representation were used for the residues of the enzyme and for the inhibitors, respectively. The pepstatin-Rhizopus pepsin complex was modeled starting from the high resolution crystal structure, where the inhibitor was in the reduced form. All pepstatin derivatives studied had modifications made on statine. The AAGlfia mutation of... 

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