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Identifying the proton loading site cluster in the ba₃ cytochrome c oxidase that loads and traps protons

Cai, Xiuhong and Son, Chang Yun and Mao, Junjun and Kaur, Divya and Zhang, Yingying and Khaniya, Umesh and Cui, Qiang and Gunner, M. R. (2020) Identifying the proton loading site cluster in the ba₃ cytochrome c oxidase that loads and traps protons. Biochimica et Biophysica Acta - Bioenergetics, 1861 (10). Art. No. 148239. ISSN 0005-2728.

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Cytochrome c Oxidase (CcO) is the terminal electron acceptor in aerobic respiratory chain, reducing O₂ to water. The released free energy is stored by pumping protons through the protein, maintaining the transmembrane electrochemical gradient. Protons are held transiently in a proton loading site (PLS) that binds and releases protons driven by the electron transfer reaction cycle. Multi-Conformation Continuum Electrostatics (MCCE) was applied to crystal structures and Molecular Dynamics snapshots of the B-type Thermus thermophilus CcO. Six residues are identified as the PLS, binding and releasing protons as the charges on heme b and the binuclear center are changed: the heme a₃ propionic acids, Asp287, Asp372, His376 and Glu126B. The unloaded state has one proton and the loaded state two protons on these six residues. Different input structures, modifying the PLS conformation, show different proton distributions and result in different proton pumping behaviors. One loaded and one unloaded protonation states have the loaded/unloaded states close in energy so the PLS binds and releases a proton through the reaction cycle. The alternative proton distributions have state energies too far apart to be shifted by the electron transfers so are locked in loaded or unloaded states. Here the protein can use active states to load and unload protons, but has nearby trapped states, which stabilize PLS protonation state, providing new ideas about the CcO proton pumping mechanism. The distance between the PLS residues Asp287 and His376 correlates with the energy difference between loaded and unloaded states.

Item Type:Article
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URLURL TypeDescription
Son, Chang Yun0000-0002-0784-6565
Cui, Qiang0000-0001-6214-5211
Additional Information:© 2020 Elsevier B.V. Received 9 January 2020, Revised 5 May 2020, Accepted 4 June 2020, Available online 10 June 2020. Research funded by grant number MCB-1519640 from the National Science Foundation. Q.C. acknowledges National Science Foundation for the grant number NSF-CHE-1829555. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Funding AgencyGrant Number
Subject Keywords:Monte Carlo sampling; Cytochrome c oxidase; Proton affinity; MCCE
Issue or Number:10
Record Number:CaltechAUTHORS:20200615-103910184
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Official Citation:Xiuhong Cai, Chang Yun Son, Junjun Mao, Divya Kaur, Yingying Zhang, Umesh Khaniya, Qiang Cui, M.R. Gunner, Identifying the proton loading site cluster in the ba3 cytochrome c oxidase that loads and traps protons, Biochimica et Biophysica Acta (BBA) - Bioenergetics, Volume 1861, Issue 10, 2020, 148239, ISSN 0005-2728, (
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:103915
Deposited By: Tony Diaz
Deposited On:15 Jun 2020 17:49
Last Modified:24 Jun 2020 21:30

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