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.