Computational studies of mechanisms underlying the reactions of enzymatic and nonenzymatic systems

Computational chemistry has been proven to be increasingly helpful and thus important when investigating chemical properties such as chemical reactivity. The hybrid quantum mechanics and molecular mechanics (QM/MM) method that exploits the advantages of both quantum mechanics (QM) and molecular mech...

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Main Author: Xu, Kai
Other Authors: Hajime Hirao
Format: Theses and Dissertations
Language:English
Published: 2017
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Online Access:http://hdl.handle.net/10356/72138
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Institution: Nanyang Technological University
Language: English
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spelling sg-ntu-dr.10356-721382023-02-28T23:58:24Z Computational studies of mechanisms underlying the reactions of enzymatic and nonenzymatic systems Xu, Kai Hajime Hirao School of Physical and Mathematical Sciences DRNTU::Science::Chemistry Computational chemistry has been proven to be increasingly helpful and thus important when investigating chemical properties such as chemical reactivity. The hybrid quantum mechanics and molecular mechanics (QM/MM) method that exploits the advantages of both quantum mechanics (QM) and molecular mechanics (MM) methods is a promising tool to gain detailed insights into complex systems such as enzymes and metal-organic frameworks (MOFs). Herein, QM/MM calculations are applied to three enzyme systems (cytochrome P450 Family 19 Subfamily A Member 1 (CYP19A1), heme oxygenase (HO), and Mo-Cu carbon monoxide dehydrogenase (MoCu CODH)) and one MOF (Cu-PDW) system, to elucidate the reaction mechanisms involved therein. For CYP19A1, the substrate was found able to act as proton source in the second step and Cpd I-driven mechanisms for the third step that well explain latest experimental observations were proposed. Ferric superoxide was found as a likely reactive species for ferric verdoheme formation in HO in the absence of a reducing equivalent and the reaction mechanism was also studied. For Mo-Cu CODH, the release of CO2 from its thiocarbonate intermediate, which was energetically difficult in DFT calculations, was found plausible in our QM/MM calculations, implying the importance of the protein environment. For the Cu-PDW MOF, CH-π interactions between substrates and the organic ligand in the MOF were identified as a key factor that leads to the enatioselectivity in the reaction studied. The mechanistic scenarios derived could provide guidelines for the development of drugs targeting CYP19A1, the engineering of the aforementioned enzymes, and the design of more efficient Cu-PDW MOFs. ​Doctor of Philosophy (SPMS) 2017-05-29T02:09:30Z 2017-05-29T02:09:30Z 2017 Thesis Xu, K. (2017). Computational studies of mechanisms underlying the reactions of enzymatic and nonenzymatic systems. Doctoral thesis, Nanyang Technological University, Singapore. http://hdl.handle.net/10356/72138 10.32657/10356/72138 en 165 p. application/pdf
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic DRNTU::Science::Chemistry
spellingShingle DRNTU::Science::Chemistry
Xu, Kai
Computational studies of mechanisms underlying the reactions of enzymatic and nonenzymatic systems
description Computational chemistry has been proven to be increasingly helpful and thus important when investigating chemical properties such as chemical reactivity. The hybrid quantum mechanics and molecular mechanics (QM/MM) method that exploits the advantages of both quantum mechanics (QM) and molecular mechanics (MM) methods is a promising tool to gain detailed insights into complex systems such as enzymes and metal-organic frameworks (MOFs). Herein, QM/MM calculations are applied to three enzyme systems (cytochrome P450 Family 19 Subfamily A Member 1 (CYP19A1), heme oxygenase (HO), and Mo-Cu carbon monoxide dehydrogenase (MoCu CODH)) and one MOF (Cu-PDW) system, to elucidate the reaction mechanisms involved therein. For CYP19A1, the substrate was found able to act as proton source in the second step and Cpd I-driven mechanisms for the third step that well explain latest experimental observations were proposed. Ferric superoxide was found as a likely reactive species for ferric verdoheme formation in HO in the absence of a reducing equivalent and the reaction mechanism was also studied. For Mo-Cu CODH, the release of CO2 from its thiocarbonate intermediate, which was energetically difficult in DFT calculations, was found plausible in our QM/MM calculations, implying the importance of the protein environment. For the Cu-PDW MOF, CH-π interactions between substrates and the organic ligand in the MOF were identified as a key factor that leads to the enatioselectivity in the reaction studied. The mechanistic scenarios derived could provide guidelines for the development of drugs targeting CYP19A1, the engineering of the aforementioned enzymes, and the design of more efficient Cu-PDW MOFs.
author2 Hajime Hirao
author_facet Hajime Hirao
Xu, Kai
format Theses and Dissertations
author Xu, Kai
author_sort Xu, Kai
title Computational studies of mechanisms underlying the reactions of enzymatic and nonenzymatic systems
title_short Computational studies of mechanisms underlying the reactions of enzymatic and nonenzymatic systems
title_full Computational studies of mechanisms underlying the reactions of enzymatic and nonenzymatic systems
title_fullStr Computational studies of mechanisms underlying the reactions of enzymatic and nonenzymatic systems
title_full_unstemmed Computational studies of mechanisms underlying the reactions of enzymatic and nonenzymatic systems
title_sort computational studies of mechanisms underlying the reactions of enzymatic and nonenzymatic systems
publishDate 2017
url http://hdl.handle.net/10356/72138
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