Supercomputer simulations reveal how kinesin steers its steps

Atomic-level supercomputer simulations have identified a physical interaction that helps direct the cellular motor kinesin as it walks along microtubule tracks. Researchers modeled kinesin bound to a microtubule and found that the motor’s flexible neck region remains close to the track surface, biasing the trailing foot to swing around the right side of the leading foot in a counterclockwise arc. This contact between the neck and microtubule was required for forward stepping in the simulations, offering a structural explanation for how kinesin controls the direction of intracellular transport.

Kinesin is a molecular motor that carries cargo through cells by moving in discrete steps along filamentous tracks called microtubules. Its two “feet,” or motor domains, must coordinate their movement so that the protein advances efficiently without leaving the track. Previous work established that a connecting segment known as the neck region is important for coordinating the feet, but its three-dimensional structure and its direct interaction with microtubules had remained unresolved because current imaging methods could not capture the relevant atomic dynamics. The new findings, published in Biophysical Journal, address that gap through all-atom molecular dynamics modeling rather than direct observation in cells.

To overcome the limitations of imaging, the team constructed an atomic model of a kinesin motor attached to a microtubule, a system containing approximately three million atoms. The simulations were performed on the Fugaku supercomputer. Using an enhanced sampling method called generalized replica exchange with solute tempering, abbreviated gREST, the researchers examined the neck region across two independently constructed computational physics models, or force fields. This approach allowed them to sample the region’s flexible conformations and determine a high-confidence structure for its most stable state. The resulting model showed that the neck contains a twisted, two-strand coiled coil positioned perpendicular to the microtubule, with part of the neck remaining in contact with the track surface.

The researchers next simulated the motor’s initial step using a simplified detachment model in which some underlying microtubule subunits were removed to trigger movement. Under these conditions, the trailing foot did not move directly over the leading foot. Instead, interactions between the neck region and the microtubule surface biased its trajectory around the right side of the forward foot, producing a counterclockwise stepping path. Control simulations supported the importance of this interaction: alternative neck configurations with weak contact against the track failed to generate forward movement. The work therefore identifies a local atomic mechanism that can connect the conformation of kinesin’s neck region with the direction of its motion. It does not demonstrate a corresponding behavior in living cells, however, because the evidence comes from computational models of a simplified motor-track system.

The study also highlights three important simplifications that constrain the model. It uses a truncated kinesin construct rather than the complete protein, artificially removes microtubule subunits to initiate stepping, and omits the flexible E-hook elements extending from the microtubule surface. The authors note that future simulations incorporating full-length kinesin and more realistic track elements could refine the proposed structural framework. Even with those limitations, the simulations provide a testable physical explanation for one of the motor’s essential functions: steering its steps. By showing how contact between a flexible molecular structure and a cellular track can bias movement, the research adds a detailed structural basis to the mechanics of intracellular cargo transport.

Subject of Research: Atomic simulations of neck–microtubule interactions that bias kinesin stepping direction

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

Article References: Supercomputer simulations reveal how the molecular motor kinesin steers itself along tracks. Original publication (Bibliographic details unavailable.)

Image Credits: AI Generated

DOI: Not provided

Keywords: kinesin, microtubules, molecular motors, supercomputing, molecular dynamics, Fugaku, intracellular transport, coiled coil, cell biology, Supercomputer, simulations, reveal