Multiscale Coarse-Grained Model for the Stepping of Molecular Motors with Application to Kinesin.

Yonathan Goldtzvik, D Thirumalai

Journal of chemical theory and computation 2021 Aug 10

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Conventional kinesin, a motor protein that transports cargo within cells, walks by taking multiple steps toward the plus end of the microtubule (MT). While significant progress has been made in understanding the details of the walking mechanism of kinesin, there are many unresolved issues. From a computational perspective, a central challenge is the large size of the system, which limits the scope of time scales accessible in standard computer simulations. Here, we create a general multiscale coarse-grained model for motors that enables us to simulate the stepping process of motors on polar tracks (actin and MT) with a focus on kinesin. Our approach greatly shortens the computation times without a significant loss in detail, thus allowing us to better describe the molecular basis of the stepping kinetics. The small number of parameters, which are determined by fitting to experimental data, allows us to develop an accurate method that may be adopted to simulate stepping in other molecular motors. The model enables us to simulate a large number of steps, which was not possible previously. We show in agreement with experiments that due to the docking of the neck linker (NL) of kinesin, sometimes deemed as the power stroke, the space explored diffusively by the tethered head is severely restricted, allowing the step to be completed in tens of microseconds. We predict that increasing the interaction strength between the NL and the motor head, achievable by mutations in the NL, decreases the stepping time but reaches a saturation value. Furthermore, the full three-dimensional dynamics of the cargo are fully resolved in our model, contributing to the predictive power and allowing us to study the important aspects of cargo-motor interactions.

Citation

Yonathan Goldtzvik, D Thirumalai. Multiscale Coarse-Grained Model for the Stepping of Molecular Motors with Application to Kinesin. Journal of chemical theory and computation. 2021 Aug 10;17(8):5358-5368