Regio- and stereoselectivity in the CYP450_BM3-catalyzed hydroxylation of complex terpenoids: a QM/MM study

Abstract

The site-selective C-H oxidation of terpenoids by P450 attracts great attention because of their wide range of biological activities. However, the binding and catalytic mechanism of P450 for hydroxylation of...

Multiscale QM/MM modelling of catalytic systems with ChemShell

“…2) are among the most studied systems using QM/MM simulations with ChemShell, and continue to be a very active topic of research. [36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51] In recent work Kalita et al used a combination of molecular dynamics simulations and QM/MM to explore oxygen binding and the protonation steps leading to formation of compound I in two archetypal P450 systems. 52 The team used these techniques also to understand the behaviour of a bioengineered CYP450 BME variant that catalyses a reaction (C-H amination) that natural P450s do not.…”

QM/MM Modeling Aided Enzyme Engineering in Natural Products Biosynthesis

“…Huang et al combined MD simulations and QM/MM calculations to study the origin of the selectivity and reactivity of P450 BM3 variants in the hydroxylation of artemisinin. 137 The conformational change of the b1 sheet was found to be crucial for reshaping the binding pocket to modulate substrate entrance and for orienting the C−H toward the oxidative species for the subsequent hydrogen abstraction. A clear correlation was observed between the activation barriers and the distances between the Fe�O group and the hydrogen to be abstracted.…”

The substrate specificity in the O-demethylation of 4-alkylguaiacols by cytochrome P450 AgcAP450

“…The side chains of arginine and lysine residues were protonated, and all of the glutamic acid and aspartic acid side chains were deprotonated. The heme-iron complex, high-valent-iron(IV)-oxo porphyrin-π-cation-radical active species, commonly known as compound I (Cpd I) is the main oxidant in cytochrome P450 enzymes 16,29,30 and hence, was used in the subsequent docking, MD and QM/MM studies.…”