Allosteric conformational change cascade in cytoplasmic dynein revealed by structure-based molecular simulations

Cytoplasmic dynein is a giant ATP-driven molecular motor that proceeds to the minus end of the microtubule (MT). Dynein hydrolyzes ATP in a ring-like structure, containing 6 AAA+ (ATPases associated with diverse cellular activities) modules, which is ~15 nm away from the MT binding domain (MTBD). This architecture implies that long-distance allosteric couplings exist between the AAA+ ring and the MTBD in order for dynein to move on the MT, although little is known about the mechanisms involved. Here, we have performed comprehensive molecular simulations of the dynein motor domain based on pre- and post- power-stroke structural information and in doing so we address the allosteric conformational changes that occur during the power-stroke and recovery-stroke processes. In the power-stroke process, the N-terminal linker movement was the prerequisite to the nucleotide-dependent AAA1 transition, from which a transition cascade propagated, on average, in a circular manner on the AAA+ ring until it reached the AAA6/C-terminal module. The recovery-stroke process was initiated by the transition of the AAA6/C-terminal, from which the transition cascade split into the two directions of the AAA+ ring, occurring both clockwise and anti-clockwise. In both processes, the MTBD conformational change was regulated by the AAA4 module and the AAA5/Strut module.Author summary: The linear molecular motor dynein is an intriguing allosteric model protein. ATP hydrolysis, catalyzed by modules in the AAA+ ring, regulates the binding to the rail molecule, microtubule, which is ~15 nm away from the AAA+ ring. The molecular mechanisms underpinning this long-distance communication are unclear. Based on recently solved pre- and post- power-stroke crystal structure information, we performed, for the first time to our knowledge, molecular simulations of complete conformational changes between the two structures. The simulation revealed that module-by-module allosteric conformational changes occur. Interestingly, the transition cascade from the pre- to the post-power-stroke states propagated in a circular manner around the AAA+ ring, while that of the recovery transitions propagated in a bi-directional manner around the ring.