QM/MM study of hydrolysis of arginine catalysed by arginase

ABSTRACT

In this paper, we have investigated the catalytic mechanism of rat liver arginase using a quantum mechanics/molecular mechanics (QM/MM) approach. The enzyme catalyses the hydrolysis of L-arginine (L-Arg) to generate L-ornithine and urea. The reaction mechanism proposed by the previous experimental studies is well reproduced by the QM/MM computations. The explicit treatment of the protein environment suggests that Glu277 fulfil its role in stabilising and orienting L-Arg before nucleophilic attack by the bridging hydroxide in the first step. We have also found that the proton transfer step involving a hydrogen bond switch is the rate-limiting step. The activation energy is computed to be 9.0 and 5.9 kcal/mol at the UB3LYP-D3/CHARMM22 and UBHandHLYP-D3/CHARMM22 levels, which are comparable to the observed activation barrier of 7.2 kcal/mol.