Symmetry-related proton transfer pathways in respiratory complex I

Significance Complex I is a redox-driven proton pump, central to aerobic energy conversion in most living organisms. To elucidate the mechanism of its pumping machinery, we need a detailed molecular picture of how access across the membrane is established and regulated. In this work we find that proton pathways in complex I form at symmetry-related locations near broken transmembrane helices. The channel opening allows influx of water molecules, catalyzing rapid Grotthuss-type proton transfer reactions. The hydration of these channels is sensitive to the protonation state of conserved buried lysine residues, which are in turn coupled to conformational changes in conserved ion pairs within each subunit. Our results provide mechanistic insight into the function of the long-range proton-pumping machinery in complex I.