Mechanisms for Flavin-Mediated Oxidation: Hydride or Hydrogen-Atom Transfer?

Area of Science:

• Biochemistry
• Quantum Chemistry
• Biophysics

Background:

• Flavins are essential biological cofactors driving proton-coupled electron transfer (PCET) reactions.
• Cellular respiration initiates with redox reactions involving nicotinamide adenine dinucleotide (NADH) and succinate oxidation, processes fundamental to energy metabolism.
• The precise mechanisms of these flavin-mediated oxidations, particularly the coupling of electron and proton transfers, remain areas of active research.

Purpose of the Study:

• To elucidate the detailed mechanisms of flavin-mediated NADH and succinate oxidation.
• To investigate the role of proton-coupled electron transfer (PCET) in these fundamental redox reactions.
• To introduce a novel computational method for quantifying electron transfer along a proton reaction coordinate.

Main Methods:

• Multiconfigurational quantum chemical calculations were employed to model the reaction pathways.
• A simplified analysis of the wave function was developed to quantify electron transfer dynamics.
• The study focused on the initial redox steps in cellular respiration involving flavins.

Main Results:

• NADH oxidation proceeds via a direct hydride transfer, where two electrons and a proton move concurrently to the acceptor.
• Succinate oxidation exhibits a more complex mechanism dependent on the elimination step, potentially involving either hydride or hydrogen atom transfer.
• In succinate oxidation, protons and electrons are transferred to different acceptor groups, unlike in NADH oxidation.

Conclusions:

• The findings differentiate the electron transfer mechanisms for NADH and succinate oxidation, clarifying debated aspects of cellular respiration.
• The developed wave function analysis provides a new diagnostic tool for characterizing electron transfer in a wide range of PCET processes.
• This research contributes to a deeper understanding of fundamental biochemical reactions and flavin cofactor function.