Electrostatic control of conformational dynamics drives proton translocation in respiratory Complex I
- 1Stockholm University
Abstract
Complex I is a large membrane protein that transduces redox energy into a proton motive force across a biological membrane, powering cellular respiration. Yet, despite significant experimental and computational efforts, its long-range proton translocation mechanism remains poorly understood. Here, we combine nuclear magnetic resonance spectroscopy and site-directed mutagenesis experiments with multiscale classical and hybrid quantum/classical (QM/MM) simulations to probe how conformational dynamics is linked to proton transfer reactions in the terminal antiporter module (Nqo12/NuoL/ND5) of Complex I. We show that protonation of a conserved proton-loading site (Lys329/His241Nqo12) in the terminal antiporter-like module gives rise to conformational changes that result in opening of the proton pathway. We further show that this protonation reaction is controlled by buried ion-pairs that modulate the barrier for proton translocation by intrinsic electric field effects. On a general level, our combined findings reveal how bioenergetic machines combine conformational dynamics with hydration transitions to establish efficient redox-driven proton pumps.
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BibTeX
@misc{liebau2026electrostatic,
title = {{Electrostatic control of conformational dynamics drives proton translocation in respiratory Complex I}},
author = {J. Liebau and P. Saura and S. Badolato and A. P. Gamiz-Hernandez and V. R. I. Kaila},
howpublished = {bioRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.03.764137},
url = {https://www.biorxiv.org/content/10.64898/2026.11.03.764137v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Electrostatic control of conformational dynamics drives proton translocation in respiratory Complex I
AU - J. Liebau
AU - P. Saura
AU - S. Badolato
AU - A. P. Gamiz-Hernandez
AU - V. R. I. Kaila
PY - 2026
DA - 2026/11/03
PB - bioRxiv
DO - 10.64898/2026.11.03.764137
UR - https://www.biorxiv.org/content/10.64898/2026.11.03.764137v1
AB - Complex I is a large membrane protein that transduces redox energy into a proton motive force across a biological membrane, powering cellular respiration. Yet, despite significant experimental and computational efforts, its long-range proton translocation mechanism remains poorly understood. Here, we combine nuclear magnetic resonance spectroscopy and site-directed mutagenesis experiments with multiscale classical and hybrid quantum/classical (QM/MM) simulations to probe how conformational dynamics is linked to proton transfer reactions in the terminal antiporter module (Nqo12/NuoL/ND5) of Complex I. We show that protonation of a conserved proton-loading site (Lys329/His241Nqo12) in the terminal antiporter-like module gives rise to conformational changes that result in opening of the proton pathway. We further show that this protonation reaction is controlled by buried ion-pairs that modulate the barrier for proton translocation by intrinsic electric field effects. On a general level, our combined findings reveal how bioenergetic machines combine conformational dynamics with hydration transitions to establish efficient redox-driven proton pumps.
ER -