Molecular Principles of Gating Proton Transport in the Antiporter Modules of Respiratory Complex I

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Abstract
The respiratory Complex I is a highly intricate redox-driven proton pump that powers oxidative phosphorylation across all domains of life. Yet, despite major efforts, its long-range energy transduction principles remain much debated. Here, we study the molecular principles of proton transport by engineering the antiporter modules of Complex I. By combining directed mutagenesis with time-resolved spectroscopy and molecular dynamics (MD) simulations, we identify conserved residues along the proton channels that control the rate of proton transfer across proteoliposome membranes. The antiporter modules catalyze this tightly regulated proton transport by transient water wires that follow intrinsic electric fields along the proton channels. Based on MD simulations, we identify conserved gating sites, established by nonpolar residues, which modulate the hydration and electric field effects underlying the proton transport upon mutation. On a general level, our findings highlight how the modular energy-transduction machinery of Complex I employs a combination of electrostatic and conformational coupling principles to catalyze long-range proton transport, with distinct similarities to other enzymes.
Funding Information
  • Vetenskapsrådet (2020-04081)
  • Vetenskapsrådet (2025- 04607)
  • Göran Gustafssons Stiftelse för Naturvetenskaplig och Medicinsk Forskning
  • Knut och Alice Wallenbergs Stiftelse (2019.025)
  • Knut och Alice Wallenbergs Stiftelse (2024.0220)
  • Knut och Alice Wallenbergs Stiftelse (WASPDDLS22:025)

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