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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United States
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Leontyev, I V; Stuchebrukhov, A A (2009) Dielectric relaxation of cytochrome c oxidase: Comparison of the microscopic and continuum models. J Chem Phys 130:085103
Stuchebrukhov, Alexei A (2009) Mechanisms of proton transfer in proteins: localized charge transfer versus delocalized soliton transfer. Phys Rev E Stat Nonlin Soft Matter Phys 79:031927
Leontyev, I V; Stuchebrukhov, A A (2009) Electronic continuum model for molecular dynamics simulations. J Chem Phys 130:085102
Sugitani, Ryogo; Medvedev, Emile S; Stuchebrukhov, Alexei A (2008) Theoretical and computational analysis of the membrane potential generated by cytochrome c oxidase upon single electron injection into the enzyme. Biochim Biophys Acta 1777:1129-39
Zheng, Xuehe; Garcia, Jorge; Stuchebrukhov, Alexei A (2008) Theoretical study of excitation energy transfer in DNA photolyase. J Phys Chem B 112:8724-9
Medvedev, E S; Kotelnikov, A I; Barinov, A V et al. (2008) Protein dynamics control of electron transfer in photosynthetic reaction centers from Rps. sulfoviridis. J Phys Chem B 112:3208-16