Reaction Mechanism of Human Renin Studied by Quantum Mechanics/Molecular Mechanics (QM/MM) Calculations

In this paper, we present the catalytic mechanism of human renin computationally investigated using an ONIOM quantum mechanics/molecular mechanics (QM/MM) methodology (B3LYP/6-31G(d):AMBER), with final energies calculated at the M06/6-311++G(2d,2p):AMBER level of theory. It was demonstrated that the full mechanism involves three sequential steps: (i) a nucleophilic attack of a water molecule on the carbonyl carbon of the scissile bond, resulting in a very stable tetrahedral gem-diol intermediate; (ii) a protonation of the peptidic bond nitrogen; and (iii) a complete breakage of the scissile bond. The activation energy barrier obtained for the angiotensinogen hydrolysis by renin was calculated as 22.0 kcal mol–1, which is consistent with the experimental value, albeit slightly larger. We have shown also that the cleavage of a mutated substrate (Val10Phe) occurs in a manner similar to that of the wild-type substrate. These results provide an understanding of the reaction catalyzed by human renin with atomistic detail. This is of particular importance because this enzyme plays a special role in the control of the renin–angiotensin system and, consequently, it is at the center of current hypertension therapy.