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

  1. Peter R. Richf,2
  1. aDepartment of Physics, University of Helsinki, FI-00014, Helsinki, Finland;
  2. bInstitute of Biotechnology, University of Helsinki, FI-00014 Helsinki, Finland;
  3. cDepartamento de Química Física I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, 28040 Madrid, Spain;
  4. dDepartamento de Química Física Aplicada, Facultad de Ciencias, Universidad Autónoma de Madrid, 28049 Madrid, Spain;
  5. eDepartment of Chemistry, King’s College London, London SE1 1DB, United Kingdom;
  6. fInstitute of Structural and Molecular Biology, University College London, London WC1E 6BT, United Kingdom
  1. Edited by Peter Brzezinski, Stockholm University, Stockholm, Sweden, and accepted by Editorial Board Member Harry B. Gray October 17, 2017 (received for review May 24, 2017)


Cytochrome oxidase is a widespread respiratory enzyme that conserves energy released when oxygen is reduced by pumping protons across the membrane in which it is located. Here, we use atomistic simulations of the whole bovine enzyme to investigate properties of the H channel, a structure that has been proposed to provide the pathway for pumped protons in mammalian forms of the enzyme. These studies show that although parts of the structure could function in this manner, a gap persists. This gap could be bridged only if a buried histidine becomes protonated. Based on these simulations, we propose that the H channel acts as a dielectric well, modulating effects of buried charge changes.


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.


  • ?1V.S. and P.G.J. contributed equally to this work.

  • ?2To whom correspondence should be addressed. Email: prr{at}ucl.ac.uk.
  • Author contributions: V.S., E.R., and P.R.R. designed research; V.S., P.G.J., and M.K. performed research; V.S., P.G.J., and E.R. analyzed data; and V.S., P.G.J., E.R., and P.R.R. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission. P.B. is a guest editor invited by the Editorial Board.

  • This article contains supporting information online at www.danielhellerman.com/lookup/suppl/doi:10.1073/pnas.1708628114/-/DCSupplemental.

Published under the PNAS license.

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