# Proton Coupled Electron Transfer Mechanism of NADH dehydrogenase, respiratory complex I

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2020 · $265,357

## Abstract

A. A. Stuchebrukhov, Electron Transfer in NADH Dehydrogenase
Proton Coupled Electron Transfer in NADH dehydrogenase: Project Summary
The goal of this computational project is to investigate fundamental principles and
atomistic details of electron tunneling along the chain of eight FeS clusters, its coupling to
proton translocation, and ultimately to uncover molecular mechanism of redox-driven
proton pumping in NADH dehydrogenase – an enzyme which is the entry point of the
electron transport chain in the respiratory system of aerobic cells (respiratory Complex I).
The work includes collaboration with leading experimental experts in the field, who
recently solved the structure of the enzyme.
We will test the hypothesis that the electron tunneling along the chain of eight FeS clusters
to the terminal FeS cluster in the peripheral part of the enzyme is coupled to a long-range
conformational change that in turn is coupled to proton translocation by the membrane
part of the enzyme; electron tunneling along the chain of FeS clusters provides a kinetic
gate necessary for operation of the conformation-driven proton pumping machine.
Mutations along the FeS chain can disrupt electron flow and render complex I
dysfunctional.
The approach is based on atomistic and quantum mechanical simulations of electron and
proton transport, using state-of-the art quantum tunneling calculations and molecular
dynamics simulations, and will involve: A1) A study of various aspects of electron tunneling
along the chain of eight FeS clusters of the enzyme, redox properties of enzymes cofactors,
and their redox reactions, prediction of the key amino acids participating in the tunneling
process; theoretical analysis of freeze-quench kinetic EPR data; A2) A study of
conformations, electrostatics, and redox-coupled protonation states of the enzyme, finding
proton transfer channels and the key groups involved in proton pumping; A3) Modeling of
the pumping mechanism.
This work is part of our long-term goal to map the whole electron transport chain in
mitochondria, to indentify molecular mechanisms of redox-driven proton pumping, oxygen
reduction, and generation of Reactive Oxygen Species (ROS). The importance of such
studies is underscored by the growing evidence that the dysfunction of the electron
transport chain in mitochondria and free radical production are contributing to cell aging,
apoptosis, and to a number of degenerative diseases of the heart and brain in humans.

## Key facts

- **NIH application ID:** 10050706
- **Project number:** 2R01GM054052-17
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** ALEXEI A STUCHEBRUKHOV
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $265,357
- **Award type:** 2
- **Project period:** 1996-05-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10050706

## Citation

> US National Institutes of Health, RePORTER application 10050706, Proton Coupled Electron Transfer Mechanism of NADH dehydrogenase, respiratory complex I (2R01GM054052-17). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10050706. Licensed CC0.

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