![]() In the c-ring, the key residues for proton transport receive and pass protons via protonation and deprotonation, respectively. (2017) confirmed that the two half-channels of the a-subunit harbor continuous spaces through which protons can pass from the matrix/IMS region to the key residues responsible for proton transport in the c-subunit. Recent cryo-electron microscopic (EM) studies have elucidated details of F O rotary mechanisms. The funnel-like space in the matrix channel is shown in pink. Water-accessible regions in the two half-channels, namely the IMS and matrix channels, are shown in yellow. The proton-carrier residue of c-subunit is cE111, the conserved arginine of a-subunit is aR239, and the representative residues of two half-channels are aE288 for the IMS channel and aE225 for the matrix channel. Representative residues with acidic, basic, and neutral side chains are indicated in red, blue, and green, respectively. Close-up (right) views of the square region in the middle cartoon. (C) Top (left) and side (middle) views of the mitochondrial F O motor a-subunit (gray), and c-ring (cyan) (PDB ID: 6F36). R + (blue) is a highly conserved arginine residue of the a-subunit. Black arrows indicate the net proton flow during ATP synthesis. Green and orange spheres represent protonated (EH) and deprotonated (E −) glutamate, respectively. (B) Cartoons showing the mechanism of proton transfer between the a-subunit and c-ring. The rotational direction of the c-ring and movement of protons required for ATP synthesis are indicated. (A) Cartoon showing the geometry of the mitochondrial F O motor. Therefore, the passage of protons through the membrane is coupled to the rotational motion of the c-ring ( Figure 1A).įigure 1. Since these two half-channels are not directly connected, protons can only pass through the membrane via rotation of the c-ring. One exchanges protons with IMS or outside the cell, and the other shuttles protons between the matrix and cytoplasm. The a-subunit possesses two half-channels. The F O motor harbors a ring-shaped c-subunit oligomer, which serves as the rotor, and an a-subunit (stator), which mediates proton transfer between the c-ring and outer membrane aqueous environment. Hybrid Monte Carlo and MD simulations showed how proton transfer is coupled to rotation.į OF 1 ATP synthase, a ubiquitous enzyme that synthesizes most ATP in living cells, comprises two rotary motors: the membrane-embedded proton-driven F O motor and the catalytic F 1 motor these motors share the central rotor and peripheral stalk. Coarse-grained MD simulations unveiled a free energy surface based on the protonation state and rotational angle of the rotor. All-atom molecular dynamics (MD) simulations elucidated changes in the protonation/deprotonation of glutamate-the protein-carrier residue-during rotation and revealed the protonation states that form the “water wire” required for long-range proton hopping. Here, we review theoretical and computational studies based on F O structure models. Despite high resolution, however, static information alone cannot elucidate how and where the protons pass through the F O and how proton passage is coupled to F O rotation. Recently, many near-atomic resolution structural models have been obtained using cryo-electron microscopy. In F OF 1 ATP synthase, driven by the proton motive force across the membrane, the F O motor rotates the central rotor and induces conformational changes in the F 1 motor, resulting in ATP synthesis. 2Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto, Japan.1Department of Anatomy and Cell Biology, McGill University, Montreal, QC, Canada.
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