Imported:YPM/Model Process page for 2007 07 03 16h24m59s

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This model was extracted on 2007/07/03. The full model documentation is available here (a zip file of the documentation is also available). The unmodified bngl file is available here.

In order to limit the scope of the model, we removed the following reaction sections from the model file:

We also removed all reactions and declarations related to pheromone, Ste2, Sst2, Gpa1, Yck, Dig1, Dig2, Ste12, Far1, and Ste50.

To reduce the complexity of the model we removed Ste20 (and its participation in any reactions).

  • To do this we assumed that the fraction of Ste4 molecules that are bound to Ste20 is taken into account by the phosphorylation rate of Ste11.
  • We altered the reactions for the phosphorylation of Ste11 such that Ste11 is phosphorylated when it is bound to Ste5 that is also bound to Ste4 (what we will call an active-G complex).
  • Rename kcat_Ste20Ste4Ste18Ste5Ste11* -> kcat_Ste4Ste18Ste5Ste11*

We also removed Kss1 from the model. Because all MAPK-dependent feedbacks are removed from this model (see below), the only effect of Kss1 is to compete with Fus3 for activation. We eliminated Kss1 to decrease the simulation time and simplify the model.

We decided to model G protein activation as a first order transition between inactive and active states of Ste4, where the rates of activation and inactivation are dependent on the pheromone dose (and will be determined by parameter estimation). The reactions for activation/inactivation of Ste4 are as follows:

Ste4(Gpa1_site~Gpa1) -> Ste4(Gpa1_site~none)

Ste4(Gpa1_site~none,Ste5_site) -> Ste4(Gpa1_site~Gpa1,Ste5_site) 

We modified the molecule type for Ste4 to include only the Ste5 binding site and the Gpa1 "modification" site. We also changed the seed species, Ste4 synthesis, and Ste4/Ste5 reactions accordingly.

For faster simulation, we removed Ste5 dimerization (and Ste5_site from Ste5). Upon removing Ste5 dimerization, we had to modify Ste11 phosphorylation of Ste7 so that it occurs in cis instead of in trans across a Ste5 dimer. None of the values of the rate constants were altered. The phosphorylation reactions for Ste7 were as follows:

Ste11(Ste5_site!2,S302_S306_T307~pS).Ste5(Ste11_site!2,Ste7_site!3).Ste7(Ste5_site!3,S359_T363~none) -> 

Ste11(Ste5_site!2,S302_S306_T307~pS).Ste5(Ste11_site!2,Ste7_site!3).Ste7(Ste5_site!3,S359_T363~pS) -> 

Ste11(Ste5_site!2,S302_S306_T307~pSpS).Ste5(Ste11_site!2,Ste7_site!3).Ste7(Ste5_site!3,S359_T363~none) -> 

Ste11(Ste5_site!2,S302_S306_T307~pSpS).Ste5(Ste11_site!2,Ste7_site!3).Ste7(Ste5_site!3,S359_T363~pS) -> 

Ste11(Ste5_site!2,S302_S306_T307~pSpSpT).Ste5(Ste11_site!2,Ste7_site!3).Ste7(Ste5_site!3,S359_T363~none) -> 

Ste11(Ste5_site!2,S302_S306_T307~pSpSpT).Ste5(Ste11_site!2,Ste7_site!3).Ste7(Ste5_site!3,S359_T363~pS) -> 

We also simplified the model by eliminating signal-dependent degradation of Ste11 and Ste7. In the presence of pheromone, both proteins have a half-life of at least 25min, so degradation shouldn't be a large factor in our simulations which extend only to about 15min. Doing so, we removed the MAPK binding site on Ste11.

We also had to change non-specific dephosphorylation of Fus3 so it only happens to free MAPK. Otherwise, for example, Fus3pY bound to phosphatase can lose a phosphate, and then there is no reaction to govern dissociation of unphosphorylated Fus3 for its phosphatases. Alternatively, we could have not altered the constitutive dephosphorylation reactions, and just added the relevant dissociation reactions.

We removed Fus3_Kss1_Kd_preference_factor, MAPK_pT_only_Kd_factor, MAPK_pT_only_PO4_factor, MAPK_pY_only_Kd_factor, and MAPK_pY_only_PO4_factor from the model as they are no longer needed.

Finally, we added a dummy parameter (appropriately called dummy_param) to be used as a control during parameter estimation.