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  Quantum Mechanics/Molecular Mechanics Insights into the Enantioselectivity of the O-Acetylation of (R,S)-Propranolol Catalyzed by Candida antarctica Lipase B

Escorcia, A. M., Sen, K., Daza, M. C., Doerr, M., & Thiel, W. (2017). Quantum Mechanics/Molecular Mechanics Insights into the Enantioselectivity of the O-Acetylation of (R,S)-Propranolol Catalyzed by Candida antarctica Lipase B. ACS Catalysis, 7(1), 115-127. doi:10.1021/acscatal.6b02310.

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cs6b02310_si_001.pdf (Supplementary material), 9MB
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Escorcia, Andrés M.1, Author
Sen, Kakali2, Author           
Daza, Martha C.1, Author
Doerr, Markus1, Author
Thiel, Walter2, Author           
Affiliations:
1Grupo de Bioquímica Teórica, Universidad Industrial de Santander, Cra 27 Calle 9, Bucaramanga, Colombia, ou_persistent22              
2Research Department Thiel, Max-Planck-Institut für Kohlenforschung, Max Planck Society, ou_1445590              

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Free keywords: Candida antarctica lipase B; enantioselectivity; enzyme catalysis; molecular dynamics; O-acylation; quantum mechanics/molecular mechanics
 Abstract: Classical molecular dynamics (MD) simulations and combined quantum mechanics/molecular mechanics (QM/MM) calculations were used to investigate the origin of the enantioselectivity of the Candida antarctica lipase B (CalB) catalyzed O-acetylation of (R,S)-propranolol. The reaction is a two-step process. The initial step is the formation of a reactive acyl enzyme (AcCalB) via a tetrahedral intermediate (TI-1). The stereoselectivity originates from the second step, when AcCalB reacts with the racemic substrate via a second tetrahedral intermediate (TI-2). Reaction barriers for the conversion of (R)- and (S)-propranolol to O-acetylpropranolol were computed for several distinct conformations of TI-2. In QM/MM geometry optimizations and reaction path calculations the QM region was described by density functional theory (B3LYP/TZVP) and the MM region by the CHARMM force field. The QM/MM calculations show that the formation of TI-2 is the rate-determining step. The energy barrier for transformation of (R)-propranolol to O-acetylpropranolol is 4.5 kcal/mol lower than that of the reaction of (S)-propranolol. Enzyme–substrate interactions were identified that play an important role in the enantioselectivity of the reaction. Our QM/MM calculations reproduce and rationalize the experimentally observed enantioselectivity in favor of (R)-propranolol. Furthermore, in contrast to what is commonly suggested for lipase-catalyzed reactions, our results indicate that the tetrahedral intermediate is not a good approximation of the corresponding transition states.

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Language(s): eng - English
 Dates: 2016-11-112016-08-122016-11-172017-01-06
 Publication Status: Published online
 Pages: 13
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1021/acscatal.6b02310
 Degree: -

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Title: ACS Catalysis
  Abbreviation : ACS Catal.
Source Genre: Journal
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Publ. Info: Washington, DC : ACS
Pages: - Volume / Issue: 7 (1) Sequence Number: - Start / End Page: 115 - 127 Identifier: Other: 2155-5435
CoNE: https://pure.mpg.de/cone/journals/resource/2155-5435