IDEAS home Printed from https://ideas.repec.org/a/plo/pcbi00/1000980.html
   My bibliography  Save this article

Monte Carlo Analysis of Neck Linker Extension in Kinesin Molecular Motors

Author

Listed:
  • Matthew L Kutys
  • John Fricks
  • William O Hancock

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.

Suggested Citation

  • Matthew L Kutys & John Fricks & William O Hancock, 2010. "Monte Carlo Analysis of Neck Linker Extension in Kinesin Molecular Motors," PLOS Computational Biology, Public Library of Science, vol. 6(11), pages 1-11, November.
  • Handle: RePEc:plo:pcbi00:1000980
    DOI: 10.1371/journal.pcbi.1000980
    as

    Download full text from publisher

    File URL: https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1000980
    Download Restriction: no

    File URL: https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1000980&type=printable
    Download Restriction: no

    File URL: https://libkey.io/10.1371/journal.pcbi.1000980?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Lépingle, D., 1995. "Euler scheme for reflected stochastic differential equations," Mathematics and Computers in Simulation (MATCOM), Elsevier, vol. 38(1), pages 119-126.
    2. Sarah Rice & Abel W. Lin & Daniel Safer & Cynthia L. Hart & Nariman Naber & Bridget O. Carragher & Shane M. Cain & Elena Pechatnikova & Elizabeth M. Wilson-Kubalek & Michael Whittaker & Edward Pate & , 1999. "A structural change in the kinesin motor protein that drives motility," Nature, Nature, vol. 402(6763), pages 778-784, December.
    3. Hongbin Li & Wolfgang A. Linke & Andres F. Oberhauser & Mariano Carrion-Vazquez & Jason G. Kerkvliet & Hui Lu & Piotr E. Marszalek & Julio M. Fernandez, 2002. "Reverse engineering of the giant muscle protein titin," Nature, Nature, vol. 418(6901), pages 998-1002, August.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Wu, Shujin & Han, Dong, 2007. "Algorithmic analysis of Euler scheme for a class of stochastic differential equations with jumps," Statistics & Probability Letters, Elsevier, vol. 77(2), pages 211-219, January.
    2. Doan Tuong-Van Le & Thomas Eckert & Günther Woehlke, 2013. "Computer Simulation of Assembly and Co-operativity of Hexameric AAA ATPases," PLOS ONE, Public Library of Science, vol. 8(7), pages 1-19, July.
    3. Takema Sasaki & Kei Saito & Daisuke Inoue & Henrik Serk & Yuki Sugiyama & Edouard Pesquet & Yuta Shimamoto & Yoshihisa Oda, 2023. "Confined-microtubule assembly shapes three-dimensional cell wall structures in xylem vessels," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    4. Chunting Zhang & Changmiao Guo & Ryan W. Russell & Caitlin M. Quinn & Mingyue Li & John C. Williams & Angela M. Gronenborn & Tatyana Polenova, 2022. "Magic-angle-spinning NMR structure of the kinesin-1 motor domain assembled with microtubules reveals the elusive neck linker orientation," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    5. Mireia Andreu-Carbó & Cornelia Egoldt & Marie-Claire Velluz & Charlotte Aumeier, 2024. "Microtubule damage shapes the acetylation gradient," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    6. Matthieu P. M. H. Benoit & Lu Rao & Ana B. Asenjo & Arne Gennerich & Hernando Sosa, 2024. "Cryo-EM unveils kinesin KIF1A’s processivity mechanism and the impact of its pathogenic variant P305L," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    7. Bo, Lijun & Yang, Xuewei, 2012. "Sequential maximum likelihood estimation for reflected generalized Ornstein–Uhlenbeck processes," Statistics & Probability Letters, Elsevier, vol. 82(7), pages 1374-1382.
    8. Ju Zhou & Anhui Wang & Yinlong Song & Nan Liu & Jia Wang & Yan Li & Xin Liang & Guohui Li & Huiying Chu & Hong-Wei Wang, 2023. "Structural insights into the mechanism of GTP initiation of microtubule assembly," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    9. Costantini, C., 1999. "Variance reduction by antithetic random numbers of Monte Carlo methods for unrestricted and reflecting diffusions," Mathematics and Computers in Simulation (MATCOM), Elsevier, vol. 51(1), pages 1-17.
    10. Hausenblas Erika, 2000. "A Numerical Scheme using Excursion Theory for Simulating Stochastic Differential Equations with Reflection and Local Time at a Boundary," Monte Carlo Methods and Applications, De Gruyter, vol. 6(2), pages 81-104, December.
    11. Guido Scarabelli & Barry J Grant, 2013. "Mapping the Structural and Dynamical Features of Kinesin Motor Domains," PLOS Computational Biology, Public Library of Science, vol. 9(11), pages 1-13, November.
    12. Gudrun Schappacher-Tilp & Timothy Leonard & Gertrud Desch & Walter Herzog, 2015. "A Novel Three-Filament Model of Force Generation in Eccentric Contraction of Skeletal Muscles," PLOS ONE, Public Library of Science, vol. 10(3), pages 1-16, March.
    13. Zhongjie Ye & Nicola Galvanetto & Leonardo Puppulin & Simone Pifferi & Holger Flechsig & Melanie Arndt & Cesar Adolfo Sánchez Triviño & Michael Palma & Shifeng Guo & Horst Vogel & Anna Menini & Clemen, 2024. "Structural heterogeneity of the ion and lipid channel TMEM16F," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    14. Tianyang Liu & Fiona Shilliday & Alexander D. Cook & Mohammad Zeeshan & Declan Brady & Rita Tewari & Colin J. Sutherland & Anthony J. Roberts & Carolyn A. Moores, 2022. "Mechanochemical tuning of a kinesin motor essential for malaria parasite transmission," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    15. Fusai, Gianluca & Luciano, Elisa, 2001. "Dynamic value at risk under optimal and suboptimal portfolio policies," European Journal of Operational Research, Elsevier, vol. 135(2), pages 249-269, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:plo:pcbi00:1000980. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: ploscompbiol (email available below). General contact details of provider: https://journals.plos.org/ploscompbiol/ .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.