Understanding the mechanics of myosin 5a through computational modelling and cryo-EM

Myosin 5a (Myo5a) is responsible for transporting cellular cargos, such as the endoplasmic reticulum, along filamentous actin (F-actin) to the periphery of cells. The lever has a key role in the function of Myo5a, however little is known about its properties in the active state, and how this contributes to Myo5a walking mechanics. In conjunction with this, neither experimental techniques, nor atomistic molecular dynamics simulations, have the appropriate spatiotemporal resolution to visualise the large-scale dynamics this motor performs (too low and too high, respectively). Fluctuating Finite Element Analysis (FFEA) is a tool that can bridge this gap. FFEA simulates protein dynamics across large spatiotemporal scales (10 nm to 500 nm, and 1 μs to 1 s) with little computational expense. This work presents a pipeline to go from cryo-EM data to a non-equilibrium FFEA model.

Cytoskeletal motors have a broad range of functions and are therefore implicated in a multitude of disease pathways. The pipeline described is broadly applicable to all cytoskeletal motors. Furthermore, this work sheds light on how nanoscale motors function in a highly viscous environment. Therefore, this research is of broad interest to medicine, fundamental biology, physics and engineering alike.