Supercomputer simulations reveal how the molecular motor kinesin steers itself along tracks

summary:

• ・　Kinesin is a vital molecular motor that transports cargoes along microtubule tracks in the cell, but atomic structural dynamics of its guiding neck region have remained unresolved.
• ・　Researchers performed massive all-atom molecular dynamics simulations on the supercomputer Fugaku to accurately model this neck region and observed its physical interactions with the microtubule surface.
• ・　The study revealed that physical contact between the neck region and the track surface directs the motor to step forward with a counterclockwise bias, providing a structural foundation for understanding fundamental intracellular transport mechanics.

Kinesin is a molecular motor responsible for hauling essential cargoes within cells by walking step-by-step along filamentous tracks known as microtubules. To move efficiently and avoid falling off, the motor's two feet must coordinate their stepping in a precise direction. Scientists have known that a connecting segment called the neck region is crucial for coordinating this motion. However, its exact three-dimensional structure and how it physically interacts with the microtubule track have remained a mystery due to the limitations of current imaging techniques.

To overcome imaging limitations, the research team built an atomic-level model of kinesin motor on a microtubule track—a system of approximately three million atoms—and simulated its dynamics on the supercomputer Fugaku. Using an enhanced sampling technique called generalized replica exchange with solute tempering (gREST) across two independent computational physics models (force fields), the researchers mapped the flexible neck region to determine its most stable structure. They then simulated the motor's initial stepping motion using a simplified detachment model where underlying microtubule subunits were removed.

The simulations revealed a high-confidence structure of the neck region, demonstrating that its twisted two-strand spiral (coiled coil) lies perpendicular to the microtubule and maintains close contact with the track surface (Fig. 1). When modeling the motor's stepping motion, the researchers found that physical interactions between the neck and the track surface strongly bias the stepping trajectory of the foot. Rather than moving straight over the top of the leading foot, the rear foot swings around the right side of the front foot along a counterclockwise path (Fig. 1b). Simulations confirmed that this specific neck-track interaction is required for forward movement, as alternative neck configurations with weak track interactions failed to step forward.

These findings explain how kinesin steers its steps at the atomic level. By resolving how local structural elements regulate movement directionality, this study offers a vital foundation for advancing understanding of cellular transport. The authors also note the next challenges of this study, which arise from three simplifications in the current model: the use of a truncated kinesin construct, the artificial removal of microtubule subunits to trigger step, and the omission of flexible structural elements (E-hooks) on the microtubule surface. Future studies incorporating full-length kinesin constructs and flexible track elements will further refine this structural framework.