 Monte Carlo Analysis of Neck Linker Extension in Kinesin Molecular MotorsMatthew L Kutys, John Fricks and William O Hancock PLOS Computational Biology, 2010, vol. 6, issue 11, 1-11 Abstract: Kinesin stepping is thought to involve both concerted conformational changes and diffusive movement, but the relative roles played by these two processes are not clear. The neck linker docking model is widely accepted in the field, but the remainder of the step – diffusion of the tethered head to the next binding site – is often assumed to occur rapidly with little mechanical resistance. Here, we investigate the effect of tethering by the neck linker on the diffusive movement of the kinesin head, and focus on the predicted behavior of motors with naturally or artificially extended neck linker domains. The kinesin chemomechanical cycle was modeled using a discrete-state Markov chain to describe chemical transitions. Brownian dynamics were used to model the tethered diffusion of the free head, incorporating resistive forces from the neck linker and a position-dependent microtubule binding rate. The Brownian dynamics and chemomechanical cycle were coupled to model processive runs consisting of many 8 nm steps. Three mechanical models of the neck linker were investigated: Constant Stiffness (a simple spring), Increasing Stiffness (analogous to a Worm-Like Chain), and Reflecting (negligible stiffness up to a limiting contour length). Motor velocities and run lengths from simulated paths were compared to experimental results from Kinesin-1 and a mutant containing an extended neck linker domain. When tethered by an increasingly stiff spring, the head is predicted to spend an unrealistically short amount of time within the binding zone, and extending the neck is predicted to increase both the velocity and processivity, contrary to experiments. These results suggest that the Worm-Like Chain is not an adequate model for the flexible neck linker domain. The model can be reconciled with experimental data if the neck linker is either much more compliant or much stiffer than generally assumed, or if weak kinesin-microtubule interactions stabilize the diffusing head near its binding site.Author Summary: Kinesin molecular motors provide a valuable model for uncovering the interplay between nanoscale mechanics and biochemistry at the level of single protein molecules. The mechanism by which kinesin motors “walk” along microtubules involves both conformational changes in the motor domains, or “heads”, as well as diffusive movements in which one head searches for its next binding site on the microtubule. This diffusive search is constrained by the 14 amino acid neck linker domain, which must be sufficiently flexible to allow the free head to diffuse forward, yet sufficiently stiff to enable mechanical communication to the rest of the molecule. We have modeled this diffusive search and integrated it into a stochastic model of the kinesin chemomechanical cycle. We find that modeling the neck linker as a Worm-Like Chain, the model most frequently used to describe unstructured polypeptide chains, results in motor behavior that conflicts with published experimental results for kinesins containing naturally or artificially extended neck linker domains. These results suggest that either the mechanical properties of the neck linker domain must be fundamentally reevaluated or that there are motor-microtubule interactions that stabilize the motor domain at its next binding site. Date: 2010 Downloads: (external link) Related works: Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text Persistent link: https://EconPapers.repec.org/RePEc:plo:pcbi00:1000980 DOI: 10.1371/journal.pcbi.1000980 Access Statistics for this article More articles in PLOS Computational Biology from Public Library of Science |
Is your work missing from RePEc? Here is how to contribute.
Questions or problems? Check the EconPapers FAQ or send mail to .
EconPapers is hosted by the
School of Business at Örebro University.