Cytochrome c oxidase (CcO) is the last enzyme in the respiratory electron transport chains of mitochondria and many aerobic bacteria. CcO catalyzes the reduction of molecular oxygen to water and uses the resultant energy to pump protons across the inner mitochondrial or bacterial cytoplasmic membrane, forming an electrochemical potential that is utilized by the cell in numerous ways, most prominently for the synthesis of ATP. The catalytic proton pumping cycle of CcO is driven by redox events, molecular oxygen binding, and O<sub>2</sub> activation in the dinuclear heme Fea3–CuB complex (DNC). Protons are delivered to the DNC via the so-called K-path. We recently obtained a new crystal structure of ba3-type CcO from Thermus thermophilus in the oxidized resting state that contains a potassium ion in the K-path in the vicinity of Tyr237 next to the DNC. Protonation of Tyr237 or formation of a Tyr237 radical during the reaction cycle may reversibly release this ion and regulate proton uptake into the DNC. Here we study the influence of this potassium ion on the structure and the pKa values of the K-path residues using density functional theory (DFT) calculations in which the protein environment is modeled via a COSMO continuum solvation model. We will show results from large DFT cluster models that combine the K-path residues and the DNC cluster. This enables us to elucidate the influence of redox and protonation states of the DNC along the reaction cycle and its interplay with the presence of the potassium ion on proton uptake via the K-path.

Insights into proton uptake in cytochrome c oxidase from DFT calculations

2019 Fall National Meeting

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