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In a cell, teams of molecular motors transport cargo through a crowded cytoskeletal environment. To gain insight into this system, we used a combination of experiment, computation and theory to examine how a team of myosin Va motors navigates a lipid vesicle through an actin intersection in 3D.

In the computational model, 1) the vesicle and actin flaments are rigid, and non-specifc interactions between the two are neglected; 2) motors are stiff springs connected to the vesicle via a compliant pivot; 3) the vesicle is ideally fluid, so unbound motors diffuse rapidly across its surface, and attached motors only experience forces normal to the vesicle's surface; 4) motors attach to actin depending on the energy cost of binding; 5) a motor, when experiencing force, steps along or detaches from the actin flament depending on the component of force along the actin flament; 6) motors usually perform 36nm steps, but occasionally take a shorter step; 7) the vesicle is in mechanical equilibrium.

Monte-Carlo simulations of this model show: 1) motor teams move the vesicle along actin in a left- handed spiral because the motors' occasional short step is less than the helical repeat distance of actin; 2) at most, three motors can be attached to actin, due to the geometry of the system and the mechanics of the motors. Our measurements of motor teams translocating a vesicle against force imposed by a laser trap support this prediction; and 3) a motor team moving along an actin flament, when presented with another actin flament oriented at 90 degrees to and spaced between 50 and 250 nm above the original actin flament, has a 33% probability of switching flaments, a 61% probability of remaining on the original flament and a 6% probability of detaching, consistent with our experimental measurements of 33%, 60% and 7%, respectively. This work suggests a mechanism by which the physical and mechanical properties of the motors, the cargo, and the actin filament landscape together ensure directed intracellular cargo transport in the face of a complex and virtually random actin cytoskeletal highway.