Mechano-Chemical Model for the Stepping of Cytoplasmic Dynein

Abstract

Cytoplasmic dynein moves processively along microtubules, but it is still unclear how its heads use the energy from ATP hydrolysis, coupled to a linker swing, to achieve directed motion. We present a theoretical model based on a winch mechanism in which the principal direction of the linker stroke is toward the microtubule rather than along it. When mechanically coupling two identical heads, each with postulated elastic properties and a minimal ATPase cycle, the model reproduces stepping with 8-nm steps and directed processivity. Depending on the strength of the interhead connection, the stepping can either be coordinated (tightly coupled heads) or uncoordinated (loosely coupled heads); in the latter case the stepping pattern shows a greater variability. The uncoordinated motor retains a high level of processivity with a reduced product release rate and at the cost of a reduced velocity. The maximum force is largely limited by the loaded motor's processivity, which depends on the product release rates, and can be as high as 6pN in uncoordinated motors. The results of our model show that the winch mechanism is in itself robust and can account for a high stall force and processivity. Its stepping efficiency, however, can be greatly improved by an attractive interaction that leads to the stacking of the two heads.