IDEAS home Printed from https://ideas.repec.org/a/plo/pone00/0108846.html
   My bibliography  Save this article

Mechanism of the Exchange Reaction in HRAS from Multiscale Modeling

Author

Listed:
  • Abhijeet Kapoor
  • Alex Travesset

Abstract

HRAS regulates cell growth promoting signaling processes by cycling between active (GTP-bound) and inactive (GDP-bound) states. Understanding the transition mechanism is central for the design of small molecules to inhibit the formation of RAS-driven tumors. Using a multiscale approach involving coarse-grained (CG) simulations, all-atom classical molecular dynamics (CMD; total of 3.02 µs), and steered molecular dynamics (SMD) in combination with Principal Component Analysis (PCA), we identified the structural features that determine the nucleotide (GDP) exchange reaction. We show that weakening the coupling between the SwitchI (residues 25–40) and SwitchII (residues 59–75) accelerates the opening of SwitchI; however, an open conformation of SwitchI is unstable in the absence of guanine nucleotide exchange factors (GEFs) and rises up towards the bound nucleotide to close the nucleotide pocket. Both I21 and Y32, play a crucial role in SwitchI transition. We show that an open SwitchI conformation is not necessary for GDP destabilization but is required for GDP/Mg escape from the HRAS. Further, we present the first simulation study showing displacement of GDP/Mg away from the nucleotide pocket. Both SwitchI and SwitchII, delays the escape of displaced GDP/Mg in the absence of GEF. Based on these results, a model for the mechanism of GEF in accelerating the exchange process is hypothesized.

Suggested Citation

  • Abhijeet Kapoor & Alex Travesset, 2014. "Mechanism of the Exchange Reaction in HRAS from Multiscale Modeling," PLOS ONE, Public Library of Science, vol. 9(10), pages 1-12, October.
    • Handle: RePEc:plo:pone00:0108846
    DOI: 10.1371/journal.pone.0108846
    as

    Download full text from publisher

    File URL: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0108846
    Download Restriction: no
    File URL: https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0108846&type=printable
    Download Restriction: no
    File URL: https://libkey.io/10.1371/journal.pone.0108846?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. P. Ann Boriack-Sjodin & S. Mariana Margarit & Dafna Bar-Sagi & John Kuriyan, 1998. "The structural basis of the activation of Ras by Sos," Nature, Nature, vol. 394(6691), pages 337-343, July.
    2. Barry J Grant & Alemayehu A Gorfe & J Andrew McCammon, 2009. "Ras Conformational Switching: Simulating Nucleotide-Dependent Conformational Transitions with Accelerated Molecular Dynamics," PLOS Computational Biology, Public Library of Science, vol. 5(3), pages 1-10, March.
    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. César Augusto F de Oliveira & Barry J Grant & Michelle Zhou & J Andrew McCammon, 2011. "Large-Scale Conformational Changes of Trypanosoma cruzi Proline Racemase Predicted by Accelerated Molecular Dynamics Simulation," PLOS Computational Biology, Public Library of Science, vol. 7(10), pages 1-7, October.
    2. Hongyang Li & Xin-Qiu Yao & Barry J Grant, 2018. "Comparative structural dynamic analysis of GTPases," PLOS Computational Biology, Public Library of Science, vol. 14(11), pages 1-19, November.
    3. Teklab Gebregiworgis & Yoshihito Kano & Jonathan St-Germain & Nikolina Radulovich & Molly L. Udaskin & Ahmet Mentes & Richard Huang & Betty P. K. Poon & Wenguang He & Ivette Valencia-Sama & Claire M. , 2021. "The Q61H mutation decouples KRAS from upstream regulation and renders cancer cells resistant to SHP2 inhibitors," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    4. Juan Manuel Ortiz-Sanchez & Sara E Nichols & Jacqueline Sayyah & Joan Heller Brown & J Andrew McCammon & Barry J Grant, 2012. "Identification of Potential Small Molecule Binding Pockets on Rho Family GTPases," PLOS ONE, Public Library of Science, vol. 7(7), pages 1-13, July.
    5. Ammu Prasanna Kumar & Suryani Lukman, 2018. "Allosteric binding sites in Rab11 for potential drug candidates," PLOS ONE, Public Library of Science, vol. 13(6), pages 1-46, June.
    6. Neeru Sharma & Uddhavesh Sonavane & Rajendra Joshi, 2020. "Comparative MD simulations and advanced analytics based studies on wild-type and hot-spot mutant A59G HRas," PLOS ONE, Public Library of Science, vol. 15(10), pages 1-22, October.
    7. Suryani Lukman & Barry J Grant & Alemayehu A Gorfe & Guy H Grant & J Andrew McCammon, 2010. "The Distinct Conformational Dynamics of K-Ras and H-Ras A59G," PLOS Computational Biology, Public Library of Science, vol. 6(9), pages 1-9, September.
    8. 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.
    9. Rudy Clausen & Buyong Ma & Ruth Nussinov & Amarda Shehu, 2015. "Mapping the Conformation Space of Wildtype and Mutant H-Ras with a Memetic, Cellular, and Multiscale Evolutionary Algorithm," PLOS Computational Biology, Public Library of Science, vol. 11(9), pages 1-26, September.

    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:pone00:0108846. 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: plosone (email available below). General contact details of provider: https://journals.plos.org/plosone/ .

    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.