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

Protonation of the conserved proton-loading site Lys329/His241Nqo12 in Complex I’s terminal antiporter-like module opens the proton pathway, linking electrostatics to conformational dynamics.

• Why it matters: The long-range mechanism by which Complex I couples conformational dynamics to proton translocation is still poorly understood, limiting mechanistic insight into redox-driven proton pumping.
• What they did: The study combines nuclear magnetic resonance spectroscopy and site-directed mutagenesis with multiscale classical and hybrid QM/MM simulations to test how protonation and buried ion-pairs affect proton transfer in the Nqo12/NuoL/ND5 module.
• The result: Buried ion-pairs modulate the barrier for proton translocation through intrinsic electric field effects, implying electrostatic control of hydration-linked conformational changes in Complex I.

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