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

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 acti...

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Detalles Bibliográficos
Autores principales: Supekar, Shreyas, Kaila, Ville R. I.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Royal Society of Chemistry 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6115622/
https://www.ncbi.nlm.nih.gov/pubmed/30310604
http://dx.doi.org/10.1039/c8sc01587b
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author Supekar, Shreyas
Kaila, Ville R. I.
author_facet Supekar, Shreyas
Kaila, Ville R. I.
author_sort Supekar, Shreyas
collection PubMed
description 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 a(3)/Cu(B) 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.
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spelling pubmed-61156222018-10-11 Dewetting transitions coupled to K-channel activation in cytochrome c oxidase Supekar, Shreyas Kaila, Ville R. I. Chem Sci Chemistry 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 a(3)/Cu(B) 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. Royal Society of Chemistry 2018-07-09 /pmc/articles/PMC6115622/ /pubmed/30310604 http://dx.doi.org/10.1039/c8sc01587b Text en This journal is © The Royal Society of Chemistry 2018 https://creativecommons.org/licenses/by-nc/3.0/This article is freely available. This article is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported Licence (CC BY-NC 3.0)
spellingShingle Chemistry
Supekar, Shreyas
Kaila, Ville R. I.
Dewetting transitions coupled to K-channel activation in cytochrome c oxidase
title Dewetting transitions coupled to K-channel activation in cytochrome c oxidase
title_full Dewetting transitions coupled to K-channel activation in cytochrome c oxidase
title_fullStr Dewetting transitions coupled to K-channel activation in cytochrome c oxidase
title_full_unstemmed Dewetting transitions coupled to K-channel activation in cytochrome c oxidase
title_short Dewetting transitions coupled to K-channel activation in cytochrome c oxidase
title_sort dewetting transitions coupled to k-channel activation in cytochrome c oxidase
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6115622/
https://www.ncbi.nlm.nih.gov/pubmed/30310604
http://dx.doi.org/10.1039/c8sc01587b
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