Interrogating Emergent Transport Properties for Molecular Motor Ensembles: A Semi-analytical Approach

Intracellular transport is an essential function in eucaryotic cells, facilitated by motor proteins—proteins converting chemical energy into kinetic energy. It is understood that motor proteins work in teams enabling unidirectional and bidirectional transport of intracellular cargo over long distances. Disruptions of the underlying transport mechanisms, often caused by mutations that alter single motor characteristics, are known to cause neurodegenerative diseases. For example, phosphorylation of kinesin motor domain at the serine residue is implicated in Huntington’s disease, with a recent study of phosphorylated and phosphomimetic serine residues indicating lowered single motor stalling forces. In this article we report the effects of mutations of this nature on transport properties of cargo carried by multiple wild-type and mutant motors. Results indicate that mutants with altered stall forces might determine the average velocity and run-length even when they are outnumbered by wild type motors in the ensemble. It is shown that mutants gain a competitive advantage and lead to an increase in the expected run-length when the load on the cargo is in the vicinity of the mutant’s stalling force or a multiple of its stalling force. A separate contribution of this article is the development of a semi-analytic method to analyze transport of cargo by multiple motors of multiple types. The technique determines transition rates between various relative configurations of motors carrying the cargo using the transition rates between various absolute configurations. This enables a computation of biologically relevant quantities like average velocity and run-length without resorting to Monte Carlo simulations. It can also be used to introduce alterations of various single motor parameters to model a mutation and to deduce effects of such alterations on the transport of a common cargo by multiple motors. Our method is easily implementable and we provide a software package for general use.Author Summary: Molecular motors such as kinesin and dynein facilitate directed transport of intracellular cargo over tracks called microtubules. Inside cells, multiple motor proteins are known to bind and move cargoes. These teams of motors enable the transport of cargoes over longer distances, extending beyond the processive runlengths of a single motor. Impaired transport, possibly due to mutations that affect single motor parameters, is known to cause neurodegenerative diseases. A recent study reported that phosphorylation of a kinesin motor implicated in Huntington’s disease, leads to a reduction in the single motor stalling force. In this work, we investigate how heterogeneity in motor stall forces can affect the coordinated transport properties of multi-motor ensembles. Our model predicts that motors with reduced stall force, even when in the minority, can determine emergent transport properties of average velocity and run-length. Under appropriate external loads, our analysis predicts that motor ensembles containing mutant motors travel longer distances, potentially contributing to the dysregulation of coordinated cargo transport, impairment of neuronal function and the onset of neurodegeneration. These results are enabled by development of a novel semi-analytic methodology to study cargo transport by multiple motors with distinct transport properties. This method is computationally less extensive than existing Monte-Carlo based approaches, easy to implement, and holds potential for understanding how individual motor proteins and properties contribute to the coordination of transport by motor ensembles.