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  2. Hydration-controlled Proton Transport In Respiratory Complex I.
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  2. Hydration-controlled Proton Transport In Respiratory Complex I.

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Hydration-Controlled Proton Transport in Respiratory Complex I.

Jong Ho Choi1, Gregory A Voth1

  • 1Department of Chemistry, Chicago Center for Theoretical Chemistry, James Franck Institute, and Institute for Biophysical Dynamics, The University of Chicago, Chicago, Illinois 60637, United States.

Journal of the American Chemical Society
|March 27, 2026

View abstract on PubMed

Summary
This summary is machine-generated.

Proton pumping in respiratory complex I is regulated by hydration. Transient water pathways facilitate proton transfer, controlling the initiation of proton pumping essential for ATP synthesis.

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Mitochondrial Respiration

Background:

  • Proton pumping by respiratory complex I is crucial for mitochondrial ATP synthesis.
  • The exact mechanism linking ubiquinone reduction to proton translocation remains unclear.
  • A proposed lateral pathway involves ND1, ND3, and ND4L subunits, with potential hydration-dependent regulation.

Purpose of the Study:

  • To elucidate the mechanism of proton translocation initiation in respiratory complex I.
  • To investigate the role of hydration in proton transfer through the proposed lateral pathway.
  • To understand the regulation of proton pumping at the molecular level.

Main Methods:

  • Multiscale reactive molecular dynamics (MS-RMD) simulations.
  • Analysis of water wire connectivity.
  • Thermodynamic feasibility assessment of proton transfer coupled to hydration.
  • Main Results:

    • Proton transfer is thermodynamically feasible under conditions of transient hydration and excess proton availability.
    • Strong coupling between local hydration and proton transfer (PT) was identified in complex I.
    • Proton injection dynamically enhances local hydration, opening the proton transfer pathway.

    Conclusions:

    • Hydration plays a critical role in regulating proton pumping in respiratory complex I.
    • The findings support a model where dynamic hydration controls the onset of proton translocation.
    • This mechanism is essential for efficient ATP synthesis in mitochondria.