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  Quantum Mechanical/Molecular Mechanical Study on the Enantioselectivity of the Enzymatic Baeyer–Villiger Reaction of 4-Hydroxycyclohexanone

Polyak, I., Reetz, M. T., & Thiel, W. (2013). Quantum Mechanical/Molecular Mechanical Study on the Enantioselectivity of the Enzymatic Baeyer–Villiger Reaction of 4-Hydroxycyclohexanone. The Journal of Physical Chemistry B, 117(17), 4993-5001. doi:10.1021/jp4018019.

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jp4018019_si_001.pdf (Supplementary material), 748KB
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Polyak, Iakov1, Author           
Reetz, Manfred T.2, 3, Author           
Thiel, Walter1, Author           
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1Research Department Thiel, Max-Planck-Institut für Kohlenforschung, Max Planck Society, ou_1445590              
2Research Department Reetz, Max-Planck-Institut für Kohlenforschung, Max Planck Society, ou_1445588              
3Fachbereich Chemie, Philipps-Universität Marburg, Hans-Meerwein-Straße, D-35032 Marburg, Germany, ou_persistent22              

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 Abstract: We report a combined quantum mechanical/molecular mechanical (QM/MM) study of the effect of mutations of the Phe434 residue in the active site of cyclohexanone monooxygenase (CHMO) on its enantioselectivity toward 4-hydroxycyclohexanone. In terms of our previously established model of the enzymatic Baeyer–Villiger reaction, enantioselectivity is governed by the preference toward the equatorial ((S)-selectivity) or axial ((R)-selectivity) conformation of the substituent at the C4 carbon atom of the cyclohexanone ring in the Criegee intermediate and the subsequent rate-limiting transition state for migration (TS2). We assess the enantiopreference by locating all relevant TS2 structures at the QM/MM level. In the wild-type enzyme we find that the axial conformation is energetically slightly more stable, thus leading to a small excess of (R)-product. In the Phe434Ser mutant, there is a hydrogen bond between the serine side chain and the equatorial substrate hydroxyl group that is retained during the whole reaction, and hence there is pronounced reverse (S)-enantioselectivity. Another mutant, Phe434Ile, is shown to preserve and enhance the (R)-selectivity. All these findings are in accordance with experiment. The QM/MM calculations allow us to explain the effect of point mutations on CHMO enantioselectivity for the first time at the molecular level by an analysis of the specific interactions between substrate and active-site environment in the TS2 structures that satisfy the basic stereoelectronic requirement of anti-periplanarity for the migrating σ-bond.

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Language(s): eng - English
 Dates: 2013-04-022013-02-202013-04-052013-05-02
 Publication Status: Issued
 Pages: 9
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 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1021/jp4018019
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Title: The Journal of Physical Chemistry B
Source Genre: Journal
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Publ. Info: Washington, D.C. : American Chemical Society
Pages: 9 Volume / Issue: 117 (17) Sequence Number: - Start / End Page: 4993 - 5001 Identifier: ISSN: 1520-6106
CoNE: https://pure.mpg.de/cone/journals/resource/1000000000293370_1