Computational methodologies for simulation of proton-coupled electron transfer in biomolecules

• Grant number: 23/00934-5
• Support Opportunities: Regular Research Grants
• Start date: September 01, 2023
• End date: August 31, 2025
• 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
• City of the host institution: São Paulo
• Associated scholarship(s): 24/08682-8 - Energetic Coupling and Structural Deactivation of Respiratory Complex I, BP.PD

Abstract

Molecular simulation is a mature research area. Its development has already been recognized in the form of Nobel Prizes and its applications in biophysics and biochemistry are widespread. However, important processes such as proton-coupled electron transfer reactions (PCET) are still less studied because of the lack of methodologies or the inadequacy of current ones. In this project we propose to implement and test a set of molecular simulation methods that will allow studies of PCET reactions in biomolecules and, thus, we will be able to investigate processes and central enzymes in cellular respiration in detail.Advanced molecular calculation and simulation methods, such as constrained molecular orbital optimization (cSCF) and modified excess charge reaction coordinate (mCEC), will be implemented and tested along with hybrid potentials of quantum chemistry and molecular mechanics (QC/MM) in the pDynamo open source library, to which we regularly contribute to develop. Our research group is a pioneer and one of the only ones in Brazil that implements and uses hybrid simulation techniques to study enzymatic mechanisms.We will apply these methodologies to study electron transport chain enzymes in mitochondria and bacteria that are equipped with prosthetic groups based on transition metals and organic coenzymes that have their redox processes modulated or associated with protonation changes. We will investigate the mechanisms of proton-coupled electron transfer 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.The research proposed here will be conducted by students and post-docs who are already members of the laboratory, in addition to the principal investigator and international collaborators in France and the USA. (AU)

Scientific publications

(4)

(The scientific publications listed on this page originate from the Web of Science or SciELO databases. Their authors have cited FAPESP grant or fellowship project numbers awarded to Principal Investigators or Fellowship Recipients, whether or not they are among the authors. This information is collected automatically and retrieved directly from those bibliometric databases.)

ARANTES, GUILHERME M.; REZAC, JAN. Benchmark of Approximate Quantum Chemical and Machine Learning Potentials for Biochemical Proton Transfer Reactions. JOURNAL OF CHEMICAL THEORY AND COMPUTATION, v. 21, n. 14, p. 11-pg., 2025-06-30. (23/00934-5)

CAMILO, SOFIA R. G.; ARANTES, GUILHERME M.. Flexibility and Hydration of the Q_o Site Determine Multiple Pathways for Proton Transfer in Cytochrome bc₁. JOURNAL OF CHEMICAL INFORMATION AND MODELING, v. 65, n. 12, p. 14-pg., 2025-06-10. (19/05531-0, 19/21856-7, 23/00934-5)

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)

ARANTES, GUILHERME M.. Redox-Activated Proton Transfer through a Redundant Network in the Q_o Site of Cytochrome bc₁. JOURNAL OF CHEMICAL INFORMATION AND MODELING, v. 65, n. 5, p. 10-pg., 2025-02-26. (23/00934-5)