Cytochrome c oxidase (CcO) is the final enzyme in the respiratory electron transport chain located in the mitochondrial membrane of animals or the periplasmic membrane of aerobic bacteria. It reduces O2 to 2H2O by the addition of 4e- + 4H+ in a series of reactions at the catalytic dinuclear complex (DNC) containing a heme a3 iron (Fea3) and a histidine coordinated Cu ion (CuB). In the intact enzyme in a membrane, the catalytic reduction cycle is linked to proton pumping across the membrane leading to a corresponding membrane electrical potential gradient. This chemiosmotic proton gradient is used by ATP synthase to synthesize ATP. We have analyzed a number of mechanistic issues related to this linkage using DFT calculations, structural, electronic, and electrostatics analyses, cycle reaction maps, molecular dynamics simulations, and new high resolution X-ray structures of the native and mutant enzymes. From this complex picture, we will extract some segments of the reaction pathway which show how protons are activated for pumping, and waters are mobilized for release.

Insights into the linkage between the catalytic reaction cycle and proton pumping in ba3 cytochrome c oxidase: combining DFT, electrostatics, molecular dynamics, and new X-ray structures

2019 Fall National Meeting

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