In Silico Model of Myosin VA-Mediated Liposome Transport Predicts Actin Filament Density and Liposome Diameter Dictate Transport Modes

Abstract

In cells, myosin Va (myoVa) motor teams transport membrane-bound cargo through three-dimensional (3D) actin filament networks; a process we modeled both in vitro and in silico by characterizing myoVa liposome transport within 3D actin networks (Lombardo et al. 2017, 2019). Here, we developed a course-grained agent-based model to predict how actin filament density and liposome diameter impact the modes of myoVa-based transport of 5,000 fluid-like liposomes through a randomly oriented actin filament network. The modes of transport were characterized as diffusive, directed, or stationary. Each simulated liposome trajectory started at the center of the actin network with the myoVa-liposome not engaged to actin, and ended after 100 seconds unless the liposome moved 10 microns within this time. As a function of actin filament density, the liposome transport modes were mostly: 1) diffusive at low density; 2) directed along actin filaments at intermediate density; 3) stationary or effectively tethered at high density as motors on the liposome surface engage with multiple actin filaments in an effective tug of war. Transition from the directed to the tethered mode of transport with increasing actin filament density arises from a percolation phase transition in the actin network, which occurs at a critical actin filament density. Below this critical density, liposomes primarily interact with single actin filaments and are thus transported in a directed manner. Above this critical density, liposomes can engage multiple actin filaments simultaneously, resulting in liposomes becoming tethered. Increasing liposome diameter decreases the critical actin filament density at which this percolation phase transition occurs. Thus, in cells, actin network density and cargo size may be regulated to match cargo delivery to the cell's physiological demands.