MD simulations and QM/MM calculations show that single-site mutations of cytochrome P450_BM3 alter the active site's complexity and the chemoselectivity of oxidation without changing the active species.

ABSTRACT: It is a long-standing mechanistic consensus that the mutation of the proton-shuttle mediator Threonine (T) in Cytochrome P450 enzymes severs the water channel and thereby quenches the formation of the active species: the high-valent iron(iv)-oxo porphyrin π-cation radical species, compound I (Cpd I). Using MD simulations and hybrid QM/MM calculations of P450_BM3 we demonstrate that this is not the case. Thus, while the original water channel is disrupted in the T268A mutant of the enzyme, a new channel is formed that generates Cpd I. With this new understanding, we address the puzzling regiochemical and kinetic-isotope effect (KIE) results (Volz et al., J. Am. Chem. Soc., 2002, 124, 9724-9725) on the sulfoxidation and N-dealkylation of dimethyl-(4-meth

SUBMITTER: Dubey KD 

PROVIDER: S-EPMC5851339 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature