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Issue 32, 2018
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Dewetting transitions coupled to K-channel activation in cytochrome c oxidase

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Abstract

Cytochrome c oxidase (CcO) drives aerobic respiratory chains in all organisms by transducing the free energy from oxygen reduction into an electrochemical proton gradient across a biological membrane. CcO employs the so-called D- and K-channels for proton uptake, but the molecular mechanism for activation of the K-channel has remained elusive for decades. We show here by combining large-scale atomistic molecular simulations with graph-theoretical water network analysis, and hybrid quantum/classical (QM/MM) free energy calculations, that the K-channel is activated by formation of a reactive oxidized intermediate in the binuclear heme a3/CuB active site. This state induces electrostatic, hydration, and conformational changes that lower the barrier for proton transfer along the K-channel by dewetting pathways that connect the D-channel with the active site. Our combined results reconcile previous experimental findings and indicate that water dynamics plays a decisive role in the proton pumping machinery in CcO.

Graphical abstract: Dewetting transitions coupled to K-channel activation in cytochrome c oxidase

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Supplementary files

Article information


Submitted
07 Apr 2018
Accepted
08 Jul 2018
First published
09 Jul 2018

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2018,9, 6703-6710
Article type
Edge Article

Dewetting transitions coupled to K-channel activation in cytochrome c oxidase

S. Supekar and V. R. I. Kaila, Chem. Sci., 2018, 9, 6703
DOI: 10.1039/C8SC01587B

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