Cytoplasmic dynein, a 1.5 MDa protein machine, mediates intracellular cargo trafficking. Powered by the hydrolysis of ATP, dynein walks along microtubules, towing cargo toward their minus ends. Despite its fundamental importance in human biology, dynein remains the least understood of all the cytoskeletal motors. Here, all-atom molecular dynamics simulations are employed to develop an atomistic description of dynein’s mechanical mechanism, beginning with characterization of the motor domain as a function of nucleotide state and microtubule contact for distinct stages of the hydrolysis cycle. Importantly, we identify changes in subdomain interfaces and dynamics distant from the active site, revealing insights into long-range allosteric communication that links hydrolysis to the conformational transitions and switches in microtubule binding affinity that underlie motor action. Our results, based on eight microseconds of simulation data, provide details that are inaccessible to experimental methods and reaffirm the need for all-atom resolution in the computational study of large-scale protein machines, despite million-atom system sizes.

Atomistic details of the dynein motor mechanism revealed by molecular dynamics simulations

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.