Computational molecular bioenergetics

• Grant number: 19/21856-7
• Support Opportunities: Regular Research Grants
• Start date: August 01, 2020
• End date: January 31, 2023
• Field of knowledge: Biological Sciences - Biophysics - Molecular Biophysics
• Principal Investigator: Guilherme Menegon Arantes
• Grantee: Guilherme Menegon Arantes
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated scholarship(s): 22/01737-6 - Training in numerical methods and administration of computational resources., BP.TT; 20/09918-4 - Technical training in numerical methods and administration of computational resources, BP.TT

Abstract

Electron transport chain enzymes in mitochondria and bacteria are equipped with transition metal-based prosthetic groups involved in essential oxidoreduction processes. In this project we propose to elucidate catalytic mechanisms and the structural stability of metal cofactors bound in these proteins. We will investigate the mechanisms of proton-electron coupled transfer (PCET) reactions of succinate and ubiquinol substrates, catalyzed by iron-sulfur clusters linked to respiratory complexes II (or succinate dehydrogenase) and III (or cytochrome bc1), respectively. We will also study the structural stability and mechanochemical activation of zinc-thiolate and cadmium-thiolate covalent bonds through the forced unfolding of the metallothionein-III protein. There is great interest in these reaction mechanisms in basic molecular and applied biophysical research for new biomaterials.We will apply and develop advanced methods in electronic structure calculation and molecular simulation, particularly hybrid potentials of quantum chemistry and molecular mechanics (QM/MM). We are pioneers and one of the only groups in Brazil that use these techniques to study enzymatic mechanisms. In particular, the computational simulation of metal complexes in solution or linked to macromolecules is still a challenge that we intend to tackle in this project by implementing new approximations for redox potential calculation and optimization of constrained molecular orbitals. The study of the forced unfolding of metallothionein-III will be conducted in direct comparison to atomic force microscopy (AFM) experiments.The research proposed here will be conducted by PhD students already members of the laboratory, as well as the principal researcher and international collaborators in France and China. (AU)

Scientific publications

(8)

(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)

VAN CLEAVE, CAMERON; KOEHN, JORDAN T.; PEREIRA, CAROLINE SIMOES; HAASE, ALLISON A.; PETERS, BENJAMIN J.; CROSLOW, SETH W.; MCLAUGHLIN, KYLE G.; WERST, KATARINA R.; GOACH, AUDRA L.; CRICK, DEAN C.; et al. Interactions of Truncated Menaquinones in Lipid Monolayers and Bilayers. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 22, n. 18, SEP 2021. (19/21856-7)

PEREIRA, CAROLINE S.; TEIXEIRA, MURILO H.; RUSSELL, DAVID A.; HIRST, JUDY; ARANTES, GUILHERME M.. Mechanism of rotenone binding to respiratory complex I depends on ligand flexibility. SCIENTIFIC REPORTS, v. 13, n. 1, p. 9-pg., 2023-04-25. (20/14542-3, 19/21856-7)

YUAN, GUODONG; CURTOLO, FELIPE; DENG, YIBING; WU, TAO; TIAN, FANG; MA, QUN; LIU, YUTONG; ZUO, JINGLIN; ARANTES, GUILHERME MENEGON; ZHENG, PENG. Highly Dynamic Polynuclear Metal Cluster Revealed in a Single Metallothionein Molecule. RESEARCH, v. 2021, JUL 14 2021. (17/26109-0, 19/21856-7, 18/08311-9)

CURTOLO, FELIPE; ARANTES, GUILHERME M.. Mechanisms for Flavin-Mediated Oxidation: Hydride or Hydrogen-Atom Transfer?. JOURNAL OF CHEMICAL INFORMATION AND MODELING, v. 60, n. 12, p. 6282-6287, DEC 28 2020. (16/23525-0, 16/24096-5, 17/26109-0, 19/21856-7)

CURTOLO, FELIPE; ARANTES, GUILHERME M.. Molecular properties and tautomeric equilibria of isolated flavins. Journal of Computational Chemistry, v. N/A, p. 12-pg., 2022-07-01. (19/21856-7, 17/26109-0)

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., 2021-04-01. (17/26109-0, 19/05531-0, 12/17833-2, 19/21856-7)

CHUNG, INJAE; WRIGHT, JOHN J.; BRIDGES, HANNAH R.; IVANOV, BOZHIDAR S.; BINER, OLIVIER; PEREIRA, CAROLINE S.; ARANTES, GUILHERME M.; HIRST, JUDY. Cryo-EM structures define ubiquinone-10 binding to mitochondrial complex I and conformational transitions accompanying Q-site occupancy. NATURE COMMUNICATIONS, v. 13, n. 1, p. 13-pg., 2022-05-19. (19/21856-7, 20/14542-3)

CURTOLO, FELIPE; ARANTES, GUILHERME M.. Dissecting Reaction Mechanisms and Catalytic Contributions in Flavoprotein Fumarate Reductases. JOURNAL OF CHEMICAL INFORMATION AND MODELING, v. 63, n. 11, p. 11-pg., 2023-05-17. (17/26109-0, 16/23525-0, 23/00934-5, 19/21856-7)