Cargo diffusion shortens single-kinesin runs at low viscous drag

Molecular motors are mechanoenzymes that actively drive long-range transport in cells. Thermal diffusion of the cargo can result in mechanical load on the motor carrying the cargo; the direction of this diffusion-based load is not correlated with motor motion. Recent single molecule-based experiments highlighted a strong asymmetric dependence of the run length of the single kinesin-1 motor on load direction, raising the intriguing possibility that thermal diffusion of the cargo may non-trivially influence the run length of the motor carrying the cargo. To test this possibility, here we employed Monte Carlo-based stochastic simulations to evaluate the transport of single-kinesin cargos over a large parameter space of physiologically relevant solution viscosities, cargo sizes, and motor velocities. Our simulations uncovered a previously unexplored, significant shortening effect of cargo diffusion on single-kinesin run length. This effect is non-monotonically influenced by viscous drag force on the cargo, which biases the effect of cargo diffusion toward the hindering direction. The non-monotonic variation of cargo run length with drag force is the direct result of the asymmetric response of kinesin’s run length to load direction. Our findings may be important for understanding the diverse characteristics of cargo transport, including run length, observed in living cells.