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bioRxiv · 10.64898/2026.11.03.764137

Electrostatic control of conformational dynamics drives proton translocation in respiratory Complex I

Liebau, J.·Saura, P.·Badolato, S.·Gamiz-Hernandez, A. P.·Kaila, V. R. I.
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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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Liebau, J., Saura, P., Badolato, S., Gamiz-Hernandez, A. P., Kaila, V. R. I.. 2026-11-04. Electrostatic control of conformational dynamics drives proton translocation in respiratory Complex I. https://doi.org/10.64898/2026.11.03.764137

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