Comparing GEF-induced GTP Binding Models - Stites 2007 Paper
Explore the comparison of GEF-induced GTP binding between the Hlavacek and Faeder models using Stites 2007 paper rates. The analysis includes adjustments, differential equations, and effects of increased SOS1 concentrations in the models, shedding light on the impact on Ras-GDP to Ras-GTP conversion and possible mutations.
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Presentation Transcript
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)
Inputting the Stites differential equation for the GEF-nt-exchange rate
The Hlavacek Model: 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! Stites paper rates into Hlavacek model: Stites paper rates into Faeder model: Increased SOS1 concentrations Parameter scan and gdat simulations Added units to be comparable to the Hlavacek model
Hlavacek Model 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 2.50E+05 2.00E+05 1.50E+05 RasGTP RasGDP 1.00E+05 5.00E+04 0.00E+00 0.00E+00 5.00E+02 1.00E+03 1.50E+03 2.00E+03 2.50E+03 3.00E+03 3.50E+03
Allosteric Binding in the Hlavacek Model: Changing Rate of Basic SOS1 2.50E+05 2.00E+05 1.50E+05 RasGTP RasGDP 1.00E+05 5.00E+04 0.00E+00 0.00E+00 5.00E+02 1.00E+03 1.50E+03 2.00E+03 2.50E+03 3.00E+03 3.50E+03
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) 2.50E+05 2.00E+05 1.50E+05 RasGTP RasGDP 1.00E+05 5.00E+04 0.00E+00 0.00E+00 5.00E+02 1.00E+03 1.50E+03 2.00E+03 2.50E+03 3.00E+03 3.50E+03
Hlavacek allosteric graph with converted rates (gdat) 2.50E+05 2.00E+05 1.50E+05 RasGTP RasGDP 1.00E+05 5.00E+04 0.00E+00 0.00E+00 5.00E+02 1.00E+03 1.50E+03 2.00E+03 2.50E+03 3.00E+03 3.50E+03
Hlavacek model with converted rates, looking at increased Sos concentration (scan) 3.00E+05 2.50E+05 2.00E+05 RasGTP RasGDP 1.50E+05 1.00E+05 5.00E+04 0.00E+00 0.00E+00 5.00E+09 1.00E+10 1.50E+10 2.00E+10 2.50E+10
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) kf kr kcat Other semi-tested mutations: Eliminated GAP (GAP-insensitive mutation) Removing the effector binding of Ras-GTP
Initial: Initial: Minimal Model with GAP insensitivity mutation rates (gdat) 9.00E+02 8.00E+02 7.00E+02 6.00E+02 5.00E+02 4.00E+02 RasAct RasGDP 3.00E+02 2.00E+02 1.00E+02 0.00E+00 0.00E+00 5.00E+02 1.00E+03 1.50E+03 2.00E+03 2.50E+03 3.00E+03 3.50E+03 -1.00E+02 -2.00E+02
Further(1): Further(1): Minimal Model with GAP insensitivity mutation rates (gdat)
Further(2): Further(2): Minimal Model with GAP insensitivity mutation rates (gdat)
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!!!
