PMID- 29133387
OWN - NLM
STAT- MEDLINE
DCOM- 20180705
LR  - 20230322
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 114
IP  - 48
DP  - 2017 Nov 28
TI  - Insights into functions of the H channel of cytochrome c oxidase from atomistic 
      molecular dynamics simulations.
PG  - E10339-E10348
LID - 10.1073/pnas.1708628114 [doi]
AB  - 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 pK(a) 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.
FAU - Sharma, Vivek
AU  - Sharma V
AUID- ORCID: 0000-0002-8838-3151
AD  - Department of Physics, University of Helsinki, FI-00014, Helsinki, Finland.
AD  - Institute of Biotechnology, University of Helsinki, FI-00014 Helsinki, Finland.
FAU - Jambrina, Pablo G
AU  - Jambrina PG
AD  - Departamento de Quimica Fisica I, Facultad de Ciencias Quimicas, Universidad 
      Complutense de Madrid, 28040 Madrid, Spain.
AD  - Departamento de Quimica Fisica Aplicada, Facultad de Ciencias, Universidad 
      Autonoma de Madrid, 28049 Madrid, Spain.
FAU - Kaukonen, Markus
AU  - Kaukonen M
AD  - Department of Physics, University of Helsinki, FI-00014, Helsinki, Finland.
FAU - Rosta, Edina
AU  - Rosta E
AD  - Department of Chemistry, King's College London, London SE1 1DB, United Kingdom.
FAU - Rich, Peter R
AU  - Rich PR
AD  - Institute of Structural and Molecular Biology, University College London, London 
      WC1E 6BT, United Kingdom prr@ucl.ac.uk.
LA  - eng
GR  - BB/L01386X/1/BB_/Biotechnology and Biological Sciences Research Council/United 
      Kingdom
GR  - BB/K001094/1/BB_/Biotechnology and Biological Sciences Research Council/United 
      Kingdom
GR  - BB/L020165/1/BB_/Biotechnology and Biological Sciences Research Council/United 
      Kingdom
GR  - BB/N007700/1/BB_/Biotechnology and Biological Sciences Research Council/United 
      Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Video-Audio Media
DEP - 20171113
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Protons)
RN  - 059QF0KO0R (Water)
RN  - 18535-39-2 (heme a)
RN  - 42VZT0U6YR (Heme)
RN  - EC 1.9.3.1 (Electron Transport Complex IV)
SB  - IM
MH  - Animals
MH  - Biological Transport, Active
MH  - Cattle
MH  - Electromagnetic Phenomena
MH  - Electron Transport/*physiology
MH  - Electron Transport Complex IV/chemistry/*physiology
MH  - Heme/*analogs & derivatives/chemistry/physiology
MH  - Ion Transport/*physiology
MH  - Mitochondria/physiology
MH  - Molecular Dynamics Simulation
MH  - *Protons
MH  - Water/chemistry/physiology
PMC - PMC5715751
OTO - NOTNLM
OT  - cell respiration
OT  - dielectric well
OT  - electron transfer
OT  - protein hydration
OT  - proton pumping
COIS- The authors declare no conflict of interest.
EDAT- 2017/11/15 06:00
MHDA- 2018/07/06 06:00
PMCR- 2018/05/28
CRDT- 2017/11/15 06:00
PHST- 2017/11/15 06:00 [pubmed]
PHST- 2018/07/06 06:00 [medline]
PHST- 2017/11/15 06:00 [entrez]
PHST- 2018/05/28 00:00 [pmc-release]
AID - 1708628114 [pii]
AID - 201708628 [pii]
AID - 10.1073/pnas.1708628114 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2017 Nov 28;114(48):E10339-E10348. doi: 
      10.1073/pnas.1708628114. Epub 2017 Nov 13.