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Mechanism of the Exchange Reaction in HRAS from Multiscale Modeling

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  • 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
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    References listed on IDEAS

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    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.
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