Mechanism of proton-powered c-ring rotation in a mitochondrial ATP synthase

• 成果类型: Article
• 署名作者: Blanc, Florian E. C.; Hummer, Gerhard
• 署名单位: Max Planck Society; Goethe University Frankfurt
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14697
• DOI: 10.1073/pnas.2314199121
• 发表日期: 2024-03-12
• 关键词: escherichia-coli; alpha-subunit; free-energies; translocation; FORCE; rotor; f1fo-atpase; f0f1-atpase; elasticity; mutations

摘要

Proton-powered c -ring rotation in mitochondrial ATP synthase is crucial to convert the transmembrane protonmotive force into torque to drive the synthesis of adenosine triphosphate (ATP). Capitalizing on recent cryo-EM structures, we aim at a structural and energetic understanding of how functional directional rotation is achieved. We performed multi-microsecond atomistic simulations to determine the free energy profiles along the c -ring rotation angle before and after the arrival of a new proton. Our results reveal that rotation proceeds by dynamic sliding of the ring over the a-subunit surface, during which interactions with conserved polar residues stabilize distinct intermediates. Ordered water chains line up for a Grotthuss-type proton transfer in one of these intermediates. After proton transfer, a high barrier prevents backward rotation and an overall drop in free energy favors forward rotation, ensuring the directionality of c -ring rotation required for the thermodynamically disfavored ATP synthesis. The essential arginine of the a-subunit stabilizes the rotated configuration through a salt bridge with the c -ring. Overall, we describe a complete mechanism for the rotation step of the ATP synthase rotor, thereby illuminating a process critical to all life at atomic resolution.