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Proc Natl Acad Sci U S A. 2017 Nov 28;114(48):E10339-E10348. doi: 10.1073/pnas.1708628114. Epub 2017 Nov 13.

Insights into functions of the H channel of cytochrome c oxidase from atomistic molecular dynamics simulations.

Author information

1
Department of Physics, University of Helsinki, FI-00014, Helsinki, Finland.
2
Institute of Biotechnology, University of Helsinki, FI-00014 Helsinki, Finland.
3
Departamento de Química Física I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, 28040 Madrid, Spain.
4
Departamento de Química Física Aplicada, Facultad de Ciencias, Universidad Autónoma de Madrid, 28049 Madrid, Spain.
5
Department of Chemistry, King's College London, London SE1 1DB, United Kingdom.
6
Institute of Structural and Molecular Biology, University College London, London WC1E 6BT, United Kingdom prr@ucl.ac.uk.

Abstract

Proton pumping A-type cytochrome c oxidase (CcO) terminates the respiratory chains of mitochondria and many bacteria. Three possible proton transfer pathways (D, K, and H channels) have been identified based on structural, functional, and mutational data. Whereas the D channel provides the route for all pumped protons in bacterial A-type CcOs, studies of bovine mitochondrial CcO have led to suggestions that its H channel instead provides this route. Here, we have studied H-channel function by performing atomistic molecular dynamics simulations on the entire, as well as core, structure of bovine CcO in a lipid-solvent environment. The majority of residues in the H channel do not undergo large conformational fluctuations. Its upper and middle regions have adequate hydration and H-bonding residues to form potential proton-conducting channels, and Asp51 exhibits conformational fluctuations that have been observed crystallographically. In contrast, throughout the simulations, we do not observe transient water networks that could support proton transfer from the N phase toward heme a via neutral His413, regardless of a labile H bond between Ser382 and the hydroxyethylfarnesyl group of heme a In fact, the region around His413 only became sufficiently hydrated when His413 was fixed in its protonated imidazolium state, but its calculated pKa is too low for this to provide the means to create a proton transfer pathway. Our simulations show that the electric dipole moment of residues around heme a changes with the redox state, hence suggesting that the H channel could play a more general role as a dielectric well.

KEYWORDS:

cell respiration; dielectric well; electron transfer; protein hydration; proton pumping

PMID:
29133387
PMCID:
PMC5715751
DOI:
10.1073/pnas.1708628114
[Indexed for MEDLINE]
Free PMC Article

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