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Computer simulation of binding and reactivity of coenzyme-Q substrates in the respiratory complex III

Grant number: 19/05531-0
Support Opportunities:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): September 01, 2019
Effective date (End): December 31, 2024
Field of knowledge:Biological Sciences - Biochemistry - Enzymology
Principal Investigator:Guilherme Menegon Arantes
Grantee:Sofia Rodrigues Guedes Camilo
Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil


The coenzyme Q: cytochrome C oxidoreductase, or respiratory complex III, catalyzes the oxidoreduction of quinols and quinones (coenzyme Q or simply Q) substrates coupled to membrane translocation of protons, in the so-called modified Q-cycle. The study of the mechanism of action of this protein complex, which is fundamental to cellular respiration and photosynthesis (by the homologous cytochrome b6f), is relevant to uncovering the molecular bases of these cellular processes, as well as to the design of biologically inspired redox catalysts and more efficient inhibitors of these enzymes. Here, we propose to use computer simulation methodologies to investigate three phenomena associated with complex III: substrate binding to the Qi and Qo sites; coupled proton and electron transfer reactions (PCET) at the Qo site; and spectroscopic signature of possible intermediates found at the Qo site, to aid in the interpretation of experimental measurements already performed. In the first one, we will use classic molecular dynamics simulation techniques and increase of configurational sampling by metadynamics. In the following two phenomena, we will also employ simulations by potential hybrids of Quantum Chemistry and Molecular Mechanics (QC/MM). Our laboratory was a pioneer in Brazil and has a lot of experience with these simulation methods. We expect to obtain profiles of free energy of complexation for the substrates and reaction at the Qo site with details of the electronic coupling PCET to determine the molecular mechanism of these phenomena and the possible existence of reaction intermediates. These results will complement ongoing efforts in our laboratory to understand the complexation and reaction mechanisms of coenzyme-Q along electron transport chains in biological systems. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
CAMILO, SOFIA R. G.; CURTOLO, FELIPE; GALASSI, VANESA V.; ARANTES, GUILHERME M.. Tunneling and Nonadiabatic Effects on a Proton-Coupled Electron Transfer Model for the Q(0) Site in Cytochrome bc(1). JOURNAL OF CHEMICAL INFORMATION AND MODELING, v. 61, n. 4, p. 10-pg., . (17/26109-0, 19/05531-0, 12/17833-2, 19/21856-7)

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