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Quantum Mechanical/Molecular Mechanical Study on the Mechanism of the Enzymatic Baeyer-Villiger Reaction

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Polyak,  Iakov
Research Department Thiel, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

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Reetz,  Manfred T.
Univ Marburg, Fachbereich Chem, D-35032 Marburg, Germany;
Research Department Reetz, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

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Thiel,  Walter
Research Department Thiel, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

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Citation

Polyak, I., Reetz, M. T., & Thiel, W. (2012). Quantum Mechanical/Molecular Mechanical Study on the Mechanism of the Enzymatic Baeyer-Villiger Reaction. Journal of the American Chemical Society, 134(5), 2732-2741. doi:10.1021/ja2103839.


Cite as: http://hdl.handle.net/11858/00-001M-0000-000E-E5B5-E
Abstract
We report a combined quantum mechanical/molecular mechanical (QM/MM) study on the mechanism of the enzymatic Baeyer–Villiger reaction catalyzed by cyclohexanone monooxygenase (CHMO). In QM/MM geometry optimizations and reaction path calculations, density functional theory (B3LYP/TZVP) is used to describe the QM region consisting of the substrate (cyclohexanone), the isoalloxazine ring of C4a-peroxyflavin, the side chain of Arg-329, and the nicotinamide ring and the adjacent ribose of NADP+, while the remainder of the enzyme is represented by the CHARMM force field. QM/MM molecular dynamics simulations and free energy calculations at the semiempirical OM3/CHARMM level employ the same QM/MM partitioning. According to the QM/MM calculations, the enzyme–reactant complex contains an anionic deprotonated C4a-peroxyflavin that is stabilized by strong hydrogen bonds with the Arg-329 residue and the NADP+ cofactor. The CHMO-catalyzed reaction proceeds via a Criegee intermediate having pronounced anionic character. The initial addition reaction has to overcome an energy barrier of about 9 kcal/mol. The formed Criegee intermediate occupies a shallow minimum on the QM/MM potential energy surface and can undergo fragmentation to the lactone product by surmounting a second energy barrier of about 7 kcal/mol. The transition state for the latter migration step is the highest point on the QM/MM energy profile. Gas-phase reoptimizations of the QM region lead to higher barriers and confirm the crucial role of the Arg-329 residue and the NADP+ cofactor for the catalytic efficiency of CHMO. QM/MM calculations for the CHMO-catalyzed oxidation of 4-methylcyclohexanone reproduce and rationalize the experimentally observed (S)-enantioselectivity for this substrate, which is governed by the conformational preferences of the corresponding Criegee intermediate and the subsequent transition state for the migration step.