Tunnel dynamics of quinone derivatives and its coupling to protein conformational rearrangements in respiratory complex I

Abstract

Respiratory complex I in mitochondria and bacteria catalyzes the transfer of electrons from NADH to quinone (Q). The free energy available from the reaction is used to pump protons and to establish a membrane proton electrochemical gradient, which drives ATP synthesis. Even though several high-resolution structures of complex I have been resolved, how Q reduction is linked with proton pumping, remains unknown. Here, microsecond long molecular dynamics (MD) simulations were performed on Yarrowia lipolytica complex I structures where Q molecules have been resolved in the ~30 Å long Q tunnel. MD simulations of several different redox/protonation states of Q reveal the coupling between the Q dynamics and the restructuring of conserved loops and ion pairs. Oxidized quinone stabilizes towards the N2 FeS cluster, a binding mode not previously described in Yarrowia lipolytica complex I structures. On the other hand, reduced (and protonated) species tend to diffuse towards the Q binding sites closer to the tunnel entrance. Mechanistic and physiological relevance of these results are discussed.

On the role of ubiquinone in the proton translocation mechanism of respiratory complex I

“…It is also interesting to note that from cryo‐EM data on mitochondrial complexes [20,56], a set of conformational changes associated with Q binding at the distal site have been identified, which may be of relevance when Q moves in the exergonic step from the proximal to the distal site. A similar yet another Q binding mode (with a hydrogen bond between Q and Tyr144 of the 49 kD subunit) is seen in the structures of bacterial complex I [20] and MD simulations of mitochondrial complex I from Y. lipolytica [65], highlighting partial convergence on Q binding modes. We thus add that this conclusion of exergonic transition of Q from the proximal to the distal site is of general importance and is also valid for mechanisms where the reduced quinol exits the tunnel and is replaced by an oxidised Q from the membrane.…”