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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

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Sen,  Kakali
Research Department Thiel, 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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cs6b02310_si_001.pdf
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Citation

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.


Cite as: http://hdl.handle.net/11858/00-001M-0000-002C-197C-B
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.