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SFB Publication on how electric fields gate proton transfer reactions in cytochrome c oxidase by Patricia Saura and Ville Kaila (SFB 1078 Mercator fellow)

In this recent publication in PNAS, Saura et al. show that internal redox changes in CcO create orientated electric fields that sort the protons along the chemical and pumping pathways, while preventing back leakage reactions.

News from Oct 13, 2022

Aerobic life is powered by membrane-bound enzymes that catalyze the transfer of electrons to oxygen and protons across a biological membrane. Cytochrome c oxidase (CcO) functions as a terminal electron acceptor in mitochondrial and bacterial respiratory chains, driving cellular respiration and transducing the free energy from O2 reduction into proton pumping. Here we show that CcO creates orientated electric fields around a nonpolar cavity next to the active site, establishing a molecular switch that directs the protons along distinct pathways. By combining large-scale quantum chemical density functional theory (DFT) calculations with hybrid quantum mechanics/molecular mechanics (QM/MM) simulations and atomistic molecular dynamics (MD) explorations, we find that reduction of the electron donor, heme a, leads to dissociation of an arginine (Arg438)–heme a3 D-propionate ion-pair. This ion-pair dissociation creates a strong electric field of up to 1 V Å−1 along a water-mediated proton array leading to a transient proton loading site (PLS) near the active site. Protonation of the PLS triggers the reduction of the active site, which in turn aligns the electric field vectors along a second, “chemical,” proton pathway. We find a linear energy relationship of the proton transfer barrier with the electric field strength that explains the effectivity of the gating process. Our mechanism shows distinct similarities to principles also found in other energy-converting enzymes, suggesting that orientated electric fields generally control enzyme catalysis.

Saura, P., Riepl, D., Frey, D.M., Wikström, M. and Kaila, V.R.I. (2022). Electric fields control water-gated proton transfer in cytochrome c oxidase. PNAS, 119, 38. doi: 10.1073/pnas.2207761119.


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