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kScience !. Comparing GEF-induced GTP binding between the Hlavacek and Faeder models, using Stites 2007 paper rates. Eitan Pearl, Stephanie Salarbux , Jennifer Nam CMACS Workshop 2014. The Stites Paper Minimal Model (no intermediate apo-Ras steps).

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Kscience

kScience!

Comparing GEF-induced GTP binding between the Hlavacek and Faeder models, using Stites 2007 paper rates

Eitan Pearl, Stephanie Salarbux, Jennifer Nam

CMACS Workshop 2014


The stites paper minimal model no intermediate apo ras steps
The Stites Paper Minimal Model(no intermediate apo-Ras steps)


Inputting the stites differential equation for the gef nt exchange rate
Inputting the Stites differential equation for the GEF-nt-exchange rate


The hlavacek model allosteric binding reactions
The HlavacekModel: Allosteric Binding Reactions

  • We added the rates for positive feedback loop – allosteric SOS1 binding (from Cell 2009)

    • Ras

      • Unbound, slow rate

    • Ras-GDP

      • Bound, intermediate rate, 5x faster

    • Ras-GTP

      • Bound, Max allosteric rate, 75x faster

  • Then compared the Hlavacek (Mass-Action) and Faeder(Minimal) Models


Hlavacek faeder models with stites rates conversions required
Hlavacek, Faeder Models with Stites’ Rates: Conversions Required!

Stites paper rates into Hlavacek model:

Stites paper rates into Faeder model:

Added units to be comparable to the Hlavacek model

  • Increased SOS1 concentrations

    • Parameter scan and gdat simulations


Hlavacek model
HlavacekModel

  • Increased SOS1 binding rates in the model to Stites paper rates/concentrations

    • Effect: turned off Ras-GDP  Ras-GTP conversion

  • Possible Mutation: Turned off GAP (GTP hydrolysis)


Allosteric binding in the hlavacek model changing rate of fast sos1
Allosteric Binding in the Hlavacek Model:Changing Rate of Fast SOS1


Allosteric binding in the hlavacek model changing rate of basic sos1
Allosteric Binding in the HlavacekModel:Changing Rate of Basic SOS1


What happens when you increase sos
What happens when you increase Sos?

  • Simulation

    • Gdat shows crossover of GTP and GDP

  • Parameter Scan

  • Interpretation: GDP began higher than GTP, but due to allosteric binding, GTP overtakes GDP.


Hlavacek original model with stites paper rates gdat
Hlavacek original model with Stites paper rates (gdat)


Hlavacek allosteric graph with converted rates gdat
Hlavacek allosteric graph with converted rates (gdat)


Hlavacek model with converted rates looking at increased sos concentration scan
Hlavacek model with converted rates, looking at increased Sos concentration (scan)


Minimal model units conversions mutation effects
Minimal Model: units conversions & mutation effects

  • Replaced minimal model concentration values with Stites paper conversions to molecules

  • Mutations

    • Removing GAP-mediated GTP hydrolysis produces a simulation gdat

    • Looked mainly at the G12V GAP insensitivity mutation (Stites 2007)

      • kfkrkcat

  • Other semi-tested mutations:

    • Eliminated GAP (GAP-insensitive mutation)

    • Removing the effector binding of Ras-GTP


Initial minimal model with gap insensitivity mutation rates gdat
Initial: Minimal Model with GAP insensitivity mutation rates (gdat)


Further 1 minimal model with gap insensitivity mutation rates gdat
Further(1): Minimal Model with GAP insensitivity mutation rates (gdat)


Further 2 minimal model with gap insensitivity mutation rates gdat
Further(2): Minimal Model with GAP insensitivity mutation rates (gdat)


Acknowledgements
Acknowledgements

Thank you to

  • Dr. Nancy Griffeth & Naralys

  • Dr. Jim Faeder

  • NSF-CMACS

  • Our fellow workshop members for collaboration!


The end any questions
The End! Any Questions?

There he goes again…

Yea sure whatever…

I’m about to run the model guys!!!


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