ArticleProceedings of the National Academy of Sciences of the United States of America2013
Changing hydration level in an internal cavity modulates the proton affinity of a key glutamate in cytochrome c oxidase.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 68 citations in OpenAlex.
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- Solvent Channels and Electric Fields Guide Proton Delivery to the Active Site of Heme Peroxidases.Angewandte Chemie (International ed. in English) · 2025Article
- Proton-Mediated PIEZO2 Channelopathy: Linking Oxaliplatin Treatment to Impaired Proprioception and Cognitive Deficits.Cancers · 2024Article
- Proton-Coupled Electron Transfer upon Oxidation of Tyrosine in a De Novo Protein: Analysis of Proton Acceptor Candidates.Biochemistry · 2024Article
- Transient water wires mediate selective proton transport in designed channel proteins.Nature chemistry · 2023Article
- Hybrid Quantum Mechanical/Molecular Mechanical Methods For Studying Energy Transduction in Biomolecular Machines.Annual review of biophysics · 2023Review
- Electric fields control water-gated proton transfer in cytochromeProceedings of the National Academy of Sciences of the United States of America · 2022Article
- Electronic Polarization Is Essential for the Stabilization and Dynamics of Buried Ion Pairs in Staphylococcal Nuclease Mutants.Journal of the American Chemical Society · 2022Article
- Structural basis for safe and efficient energy conversion in a respiratory supercomplex.Nature communications · 2022Article
- A quantitative paradigm for water-assisted proton transport through proteins and other confined spaces.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- O to bR transition in bacteriorhodopsin occurs through a proton hole mechanism.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Biomolecular QM/MM Simulations: What Are Some of the "Burning Issues"?The journal of physical chemistry. B · 2021Article
- Protein Motifs for Proton Transfers That Build the Transmembrane Proton Gradient.Frontiers in chemistry · 2021Review
- Salt bridges govern the structural heterogeneity of heme protein interactions and porphyrin networks: microperoxidase-11.RSC advances · 2020Article
- On the control of the proton current in the voltage-gated proton channel Hv1.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Dewetting transitions coupled to K-channel activation in cytochromeChemical science · 2018Article
- Water is an active matrix of life for cell and molecular biology.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Cavity hydration dynamics in cytochromeProceedings of the National Academy of Sciences of the United States of America · 2017Article
- Water exit pathways and proton pumping mechanism in B-type cytochrome c oxidase from molecular dynamics simulations.Biochimica et biophysica acta · 2016Article
- Multiscale simulations reveal key features of the proton-pumping mechanism in cytochrome c oxidase.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Cytochrome c oxidase contributes to the transmembrane proton gradient by removing two protons from the high-pH side of the membrane each time the binuclear center active site is reduced. One proton goes to the binuclear center, whereas the other is pumped to the low-pH periplasmic space. Glutamate 286 (Glu286) has been proposed to serve as a transiently deprotonated proton donor. Using unrestrained atomistic molecular dynamics simulations, we show that the size of and water distribution in the hydrophobic cavity that holds Glu286 is controlled by the protonation state of the propionic acid of heme a3, a group on the proton outlet pathway. Protonation of the propionate disrupts hydrogen bonding to two side chains, allowing a loop to swing open. Continuum electrostatics and atomistic free-energy perturbation calculations show that the resultant changes in hydration and electrostatic interactions lower the Glu proton affinity by at least 5 kcal/mol. These changes in the internal hydration level occur in the absence of major conformational transitions and serve to stabilize needed transient intermediates in proton transport. The trigger is not the protonation of the Glu of interest, but rather the protonation of a residue ∼10 Å away. Thus, unlike local water penetration to stabilize a new charge, this finding represents a specific role for water molecules in the protein interior, mediating proton transfers and facilitating ion transport.
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