Reaction mechanisms of flavins and flavoproteins from an electronic-structure perspective (2022)
- Authors:
- Autor USP: CURTOLO, FELIPE - IQ
- Unidade: IQ
- Sigla do Departamento: QBQ
- DOI: 10.11606/T.46.2022.tde-15022023-180438
- Assunto: ESTRUTURA ELETRÔNICA
- Keywords: Benchmark study; Cálculos de estrutura eletrônica; Electronic-structure calculation; Estudo comparativo; Flavin; Flavina; Flavoprotein; Flavoproteína; Fumarate reductase; Fumarato redutase; Mecanismo de reação; Reaction mechanism
- Agências de fomento:
- Language: Inglês
- Abstract: Proteins equipped with flavin adenine dinucleotides (FAD) or flavin mononucleotides (FMN) are named flavoproteins and constitute about 1% of all existing proteins. They catalyze redox, acid-base and photochemical reactions in a variety of biochemical phenomena that goes from energy metabolism to DNA repair and light sensing. The versatility observed in flavoproteins is ultimately a balance of flavin intrinsic properties modulated by a protein environment. This thesis aims to investigate how flavoproteins work by systematic evaluating flavin properties and reactivity. In particular, the mechanism of fumarate reduction by the flavoenzyme fumarate reductase Fcc3 was determined. Electronic-structure calculations were used for this task based on rigorous calibration with experimental data and error assessment. Flavin properties at chemical accuracy were obtained with single reference coupled-cluster CCSD(T) calculations at the complete basis set limit. Density functional theory was demonstrated an excellent alternative with lower computational costs and slightly less accuracy. Flavin protonation and tautomerism were shown to be important modulators of flavin properties and reactivity, with the possibility of various tautomers existing at neutral pH. Regarding flavin redox properties, an analysis based on multiconfigurational wave function weights was proposed for categorizing flavin redox reactions as hydride or hydrogen-atom transfers. This analysis is an upgrade over traditional partial charges methods and can be applied not only to flavin reactions but to any protoncoupled electron transfer. In the investigation of the enzymatic mechanism of fumarate reduction, the reaction was determined as a nucleophilic addition by hydride transfer with carbanion formation. Fumarate reductase employs electrostatic catalysis in contrast to previous proposals of substrate straining and general-acid catalysis.Also, hydride transfer was shown to be vibronically adiabatic with low tunneling contribution. These findings give new insights into the mechanisms of fumarate reductases and provide a framework for future computational studies of flavoproteins in general. The analyses and benchmark studies presented can be used to build better models of properties and reactivity of flavins and flavoproteins
- Imprenta:
- Data da defesa: 18.11.2022
- Status:
- Artigo publicado em periódico de acesso aberto (Gold Open Access)
- Versão do Documento:
- Versão publicada (Published version)
- Acessar versão aberta:
-
ABNT
CURTOLO, Felipe. Reaction mechanisms of flavins and flavoproteins from an electronic-structure perspective. 2022. Tese (Doutorado) – Universidade de São Paulo, São Paulo, 2022. Disponível em: https://teses.usp.br/teses/disponiveis/46/46131/tde-15022023-180438/. Acesso em: 08 abr. 2026. -
APA
Curtolo, F. (2022). Reaction mechanisms of flavins and flavoproteins from an electronic-structure perspective (Tese (Doutorado). Universidade de São Paulo, São Paulo. Recuperado de https://teses.usp.br/teses/disponiveis/46/46131/tde-15022023-180438/ -
NLM
Curtolo F. Reaction mechanisms of flavins and flavoproteins from an electronic-structure perspective [Internet]. 2022 ;[citado 2026 abr. 08 ] Available from: https://teses.usp.br/teses/disponiveis/46/46131/tde-15022023-180438/ -
Vancouver
Curtolo F. Reaction mechanisms of flavins and flavoproteins from an electronic-structure perspective [Internet]. 2022 ;[citado 2026 abr. 08 ] Available from: https://teses.usp.br/teses/disponiveis/46/46131/tde-15022023-180438/ - Mechanisms for Flavin-mediated oxidation: hydride or hydrogen-atom transfer?
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