The goal of this computational project is to advance understanding of the molecular mechanism of NADH dehydrogenase (Complex I) - an enzyme which is the entry point of the electron transport chain in the respiratory system of aerobic cells. It has been established that the enzyme pumps 4 protons per 2 electrons of each NADH oxidized, however the molecular mechanism of proton pumping remains unknown. The work includes collaboration with a leading experimental expert in the field, who recently solved the structure of the enzyme. We will test the hypothesis that electron tunneling along the chain of seven FeS clusters in the peripheral arm of the enzyme is coupled to a long-range conformational change which in turn is coupled to proton translocation in the membrane part of the enzyme;the conformational change is presumably induced by the dissociation of one of the cysteine ligands to the terminal N2 FeS center upon its reduction;the local structural relaxation around N2 is transmitted to the membrane part of the enzyme, and induces allosteric change responsible for proton pumping;the time-limiting step of electron tunneling along the chain of FeS clusters provides a kinetic gate necessary for operation of this conformation-driven proton pumping machine. 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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Macromolecular Structure and Function A Study Section (MSFA)
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Anderson, Vernon
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University of California Davis
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Stuchebrukhov, Alexei A (2018) Redox-Driven Proton Pumps of the Respiratory Chain. Biophys J 115:830-840
Hagras, Muhammad A; Stuchebrukhov, Alexei A (2016) Internal switches modulating electron tunneling currents in respiratory complex III. Biochim Biophys Acta 1857:749-58
Morozenko, A; Stuchebrukhov, A A (2016) Dowser++, a new method of hydrating protein structures. Proteins 84:1347-57
Hagras, Muhammad A; Stuchebrukhov, Alexei A (2016) Novel Inhibitors for a Novel Binding Site in Respiratory Complex III. J Phys Chem B 120:2701-8
Samudio, Benjamin M; Couch, Vernon; Stuchebrukhov, Alexei A (2016) Monte Carlo Simulations of Glu-242 in Cytochrome c Oxidase. J Phys Chem B 120:2095-105
Stuchebrukhov, Alexei (2016) Tunneling Time and the Breakdown of Born-Oppenheimer Approximation. J Phys Chem B 120:1408-17
Hagras, Muhammad A; Hayashi, Tomoyuki; Stuchebrukhov, Alexei A (2015) Quantum Calculations of Electron Tunneling in Respiratory Complex III. J Phys Chem B 119:14637-51
Hagras, Muhammad A; Stuchebrukhov, Alexei A (2015) Transition Flux Formula for the Electronic Coupling Matrix Element. J Phys Chem B 119:7712-21
Leontyev, Igor V; Stuchebrukhov, Alexei A (2014) Polarizable molecular interactions in condensed phase and their equivalent nonpolarizable models. J Chem Phys 141:014103
Medvedev, E S; Stuchebrukhov, A A (2014) Mechanisms of generation of local ?pH in mitochondria and bacteria. Biochemistry (Mosc) 79:425-34

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