Molecular and energetic basis of histidine switch dynamics in respiratory complex I.

The respiratory complex I in mitochondria and bacteria drives the two-electron reduction of quinone to pump protons across the membrane. The molecular basis of this catalytic reaction remains enigmatic despite significant progress in structural characterization of the complex. A highly conserved histidine residue in the distal antiporter-like subunit of its membrane domain has been shown to undergo conformational changes in molecular simulations and cryo-EM structures. However, the function of histidine switch dynamics and the energetics of its conformational transitions remain unclear. Here, by applying enhanced sampling classical molecular dynamics simulations, we evaluate the energetics of the histidine switch dynamics and demonstrate that it is coupled to the tautomeric state of histidine and to the charge state of lysine residues ca. 10 Å apart, which cause hydrogen bond restructuring and stabilize the histidine residue in specific conformations. Hybrid QM/MM metadynamics-based free energy simulations show that the histidine switch participates in gated proton transfer and may function as a proton confurcation device in complex I and related proteins.