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 energetics of its conformational transitions remain unclear. Here, by applying enhanced sampling simulations, we evaluate the energetics of the histidine switch dynamics and demonstrate that it is coupled to the charge state of lysine residues ca. 10 [A] apart, which cause hydrogen bond restructuring and stabilize histidine in specific conformations. Hybrid QM/MM metadynamics simulations show that the histidine participates in gated proton transfer and may function as a proton confurcation device in complex I and related proteins. Importance of workProton pumping by the mitochondrial respiratory chain enzymes needs to be highly directional so that the ATP production occurs as efficiently as possible during high energy demands. With the protons being hard to detect by most methods of structural biology, computer simulation approaches as applied in this work offer critical information on how molecular gates within respiratory complexes can function and help elucidate the challenging questions in the field of mitochondrial bioenergetics.