Quantum Mechanics/Molecular Mechanics Insights into the Enantioselectivity of the O-Acetylation of (R,S)-Propranolol Catalyzed by Candida antarctica Lipase B
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 proce...
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ftpubman:oai:pure.mpg.de:item_2368408 2024-09-15T17:47:55+00:00 Quantum Mechanics/Molecular Mechanics Insights into the Enantioselectivity of the O-Acetylation of (R,S)-Propranolol Catalyzed by Candida antarctica Lipase B Escorcia, A. Sen, K. Daza, M. Doerr, M. Thiel, W. 2017-01-06 application/pdf http://hdl.handle.net/11858/00-001M-0000-002C-197C-B http://hdl.handle.net/11858/00-001M-0000-002C-197E-7 eng eng info:eu-repo/semantics/altIdentifier/doi/10.1021/acscatal.6b02310 http://hdl.handle.net/11858/00-001M-0000-002C-197C-B http://hdl.handle.net/11858/00-001M-0000-002C-197E-7 ACS Catalysis info:eu-repo/semantics/article 2017 ftpubman https://doi.org/10.1021/acscatal.6b02310 2024-07-31T09:31:26Z 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. Article in Journal/Newspaper Antarc* Antarctica Max Planck Society: MPG.PuRe ACS Catalysis 7 1 115 127 |
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English |
description |
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. |
format |
Article in Journal/Newspaper |
author |
Escorcia, A. Sen, K. Daza, M. Doerr, M. Thiel, W. |
spellingShingle |
Escorcia, A. Sen, K. Daza, M. Doerr, M. Thiel, W. Quantum Mechanics/Molecular Mechanics Insights into the Enantioselectivity of the O-Acetylation of (R,S)-Propranolol Catalyzed by Candida antarctica Lipase B |
author_facet |
Escorcia, A. Sen, K. Daza, M. Doerr, M. Thiel, W. |
author_sort |
Escorcia, A. |
title |
Quantum Mechanics/Molecular Mechanics Insights into the Enantioselectivity of the O-Acetylation of (R,S)-Propranolol Catalyzed by Candida antarctica Lipase B |
title_short |
Quantum Mechanics/Molecular Mechanics Insights into the Enantioselectivity of the O-Acetylation of (R,S)-Propranolol Catalyzed by Candida antarctica Lipase B |
title_full |
Quantum Mechanics/Molecular Mechanics Insights into the Enantioselectivity of the O-Acetylation of (R,S)-Propranolol Catalyzed by Candida antarctica Lipase B |
title_fullStr |
Quantum Mechanics/Molecular Mechanics Insights into the Enantioselectivity of the O-Acetylation of (R,S)-Propranolol Catalyzed by Candida antarctica Lipase B |
title_full_unstemmed |
Quantum Mechanics/Molecular Mechanics Insights into the Enantioselectivity of the O-Acetylation of (R,S)-Propranolol Catalyzed by Candida antarctica Lipase B |
title_sort |
quantum mechanics/molecular mechanics insights into the enantioselectivity of the o-acetylation of (r,s)-propranolol catalyzed by candida antarctica lipase b |
publishDate |
2017 |
url |
http://hdl.handle.net/11858/00-001M-0000-002C-197C-B http://hdl.handle.net/11858/00-001M-0000-002C-197E-7 |
genre |
Antarc* Antarctica |
genre_facet |
Antarc* Antarctica |
op_source |
ACS Catalysis |
op_relation |
info:eu-repo/semantics/altIdentifier/doi/10.1021/acscatal.6b02310 http://hdl.handle.net/11858/00-001M-0000-002C-197C-B http://hdl.handle.net/11858/00-001M-0000-002C-197E-7 |
op_doi |
https://doi.org/10.1021/acscatal.6b02310 |
container_title |
ACS Catalysis |
container_volume |
7 |
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1 |
container_start_page |
115 |
op_container_end_page |
127 |
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1810497639037272064 |