Theoretical and computational study of electron transport and redox-driven proton

University Of California At Davis, Davis CA

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Abstract

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.