Computational Characterization of the Reactivity of Compound I in Unspecific Peroxygenases

Costa, Gustavo J.; Egbemhenghe, Abel; Liang, Ruibin

doi:10.1021/acs.jpcb.3c06311

Cited by 1 publication

(1 citation statement)

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“…According to previous literature on cytochrome P450 enzymes, , the UB3LYP functional is able to reproduce the relative spin state energies, excitation energies, and spin coupling from the correlated ab initio treatment quite well. Besides, the UB3LYP functional has been well benchmarked and employed for describing the reactivities and electronic structures of P450 enzymes, and its accuracy has also been validated . For geometry optimizations, a smaller basis set of LANL2DZ , for iron along with 6-31G(d,p) for other atoms was applied, while for single point energy calculations, a larger basis set of LANL2TZf for iron and 6-311++G(2d,2p) for other atoms was applied to get more accurate energies of the system.…”

Section: Computational Methodsmentioning

confidence: 99%

Multiscale Study on the Intramolecular C–S Bond Formation Catalyzed by P450 Monooxygenase CxnD Involved in the Biosynthesis of Chuangxinmycin: The Critical Roles of Noncrystal Water Molecule and Conformational Change

Li,

Liu

2024

Inorg. Chem.

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Cytochrome P450 monooxygenase CxnD catalyzes intramolecular C−S bond formation in the biosynthesis of chuangxinmycin, which is representative of the synthesis of sulfur-containing natural heterocyclic compounds. The intramolecular cyclization usually requires the activation of two reaction sites and a large conformational change; thus, illuminating its detailed reaction mechanism remains challengeable. Here, the reaction pathway of CxnD-catalyzed C−S bond formation was clarified by a series of calculations, including Gaussian accelerated molecular dynamics simulations and quantum mechanical-molecular mechanical calculations. Our results revealed that the C−S formation follows a diradical coupling mechanism. CxnD first employs Cpd I to abstract the hydrogen atom from the imino group of the indole ring, and then, the resulted Cpd II further extracts another hydrogen atom from the thiol group of the side chain to afford a diradical intermediate, in which a noncrystal water molecule entering into the active site after the formation of Cpd I was proved to play an indispensable role. Moreover, the diradical intermediate cannot directly perform the coupling reaction. It should first undergo a series of conformational changes leading to the proximity of two reaction sites. It is the flexibility of the active site of the enzyme and the side chain of the substrate that makes the diradical coupling to be successful.

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