The Activation and Deactivation of Ras By Random

The Activation and Deactivation of Ras By Random Kamil, Ruiyan, and Alina

The Model u Faeder Model u Positive Feedback loop with SOS rate dependence on allosteric binding of activated RAS u Michaelis Menten SOS catalyzed nucleotide exchange u Hlavacek Model u Single Step reactions for SOS catalyzed nucleotide exchange u Existence of Empty RAS

Ras GTP Activation Threshold • With positive feedback: 2. 10 x 10 -8 M • Without positive feedback: 7. 4 x 10 -8 M

Effect of positive feedback loop with 12, 000 molecules of SOS No Positive Feedback

Number of SOS Molecules: 2. 0 e-10*NA*V*600 72, 000 Signal causes SOS to be recruited to the membrane

Number of SOS Molecules: 2. 0 e-10*NA*V*60 7, 200 SOS is no longer being recruited

SOS number of molecules: 2. 0 e-10*NA*V*20 2, 400 Even more SOS leaves the membrane area

Comparing Models with different observables Ras GTP and GDP bound to any molecule Ras GTP and GDP Alone with less effector binding Ras GTP and GDP Alone

Effector Activation High SOS Low SOS

The Ras Mutation • Ras still binds to gap, but gap is unable to hydrolyze GTP • Slow intrinsic hydrolysis still occurs The Ideal Drug • Binds to mutated Ras and gap can now do its job assisting hydrolysis

Activating Thresholds for Mutated Ras • Mutated Ras with no drug: 1 x 10 -8 M • Mutated Ras with drug: 2. 50 x 10 -8 M

Mutated Ras Low SOS Concentration (2. 0 e-10*NA*V*60) molecules 7, 200 molecules Ras GTP dominates

Mutated Ras with Drug Low SOS Concentration (2. 0 e-10*NA*V*60) molecules 7, 200 molecules System is turned off Ras GDP Dominates

Acknowledgement We want to thank Dr. Jim Faeder and Dr. William Hlavacek for providing us with the model. We also want to show our deepest appreciation to Dr. Nancy Griffeth and for Ms. Naralys Batista for their support on our project as well as the entire CMACS workshop