A physical model describing the transport mechanisms of cytoplasmic dynein

Cytoplasmic dynein 1 is crucial for many cellular processes including endocytosis and cell division. Dynein malfunction can lead to neurodevelopmental and neurodegenerative disease, such as intellectual disability, Charcot-Marie-Tooth disease and spinal muscular atrophy with lower extremity predominance. We formulate, based on physical principles, a mechanical model to describe the stepping behaviour of cytoplasmic dynein walking on microtubules. Unlike previous studies on physical models of this nature, we base our formulation on the whole structure of dynein to include the temporal dynamics of the individual components such as the cargo (for example an endosome or bead), two rings of six ATPase domains associated with diverse cellular activities and the microtubule binding domains. This mathematical framework allows us to examine experimental observations across different species of dynein as well as being able to make predictions (not currently experimentally measured) on the temporal behaviour of the individual components of dynein. Initially, we examine a continuous model using plausible force functions to model the ATP force and binding affinity to the microtubule. Our results show hand-over-hand and shuffling stepping patterns in agreement with experimental observations. We are able to move from a hand-overhand to a shuffling stepping pattern by changing a single parameter. We also explore the effects of multiple motors. Next, we explore stochasticity within the model, modelling the binding of ATP as a random event. Our results reflect experimental observations that dynein walks using a predominantly shuffling stepping pattern. Furthermore, we study the effects of mutated dynein and extend the model to include variable step sizes, backward stepping and dwelling. Independent stepping is studied and the results show that coordinated stepping is needed in order to obtain experimental run lengths.