# Reduced state-space version of EGFR_NET.BNGL with equivalent ODE dynamics begin model begin parameters egf_tot 1.2e6 # molecule counts egfr_tot 1.8e5 # molecule counts Grb2_tot 1.0e5 # molecule counts Shc_tot 2.7e5 # molecule counts Sos_tot 1.3e4 # molecule counts Grb2_Sos_tot 4.9e4 # molecule counts kp1 1.667e-06 # ligand-monomer binding (scaled), units: /molecule/s km1 0.06 # ligand-monomer dissociation, units: /s kp2 5.556e-06 # aggregation of bound monomers (scaled), units: /molecule/s km2 0.1 # dissociation of bound monomers, units: /s kp3 0.5 # dimer transphosphorylation, units: /s km3 4.505 # dimer dephosphorylation, units: /s kp14 3 # Shc transphosphorylation, units: /s km14 0.03 # Shc dephosphorylation, units: /s km16 0.005 # Shc cytosolic dephosphorylation, units: /s kp9 8.333e-07 # binding of Grb2 to receptor (scaled), units: /molecule/s km9 0.05 # dissociation of Grb2 from receptor, units: /s kp10 5.556e-06 # binding of Sos to receptor (scaled), units: /molecule/s km10 0.06 # dissociation of Sos from receptor, units: /s kp11 1.25e-06 # binding of Grb2-Sos to receptor (scaled), units: /molecule/s km11 0.03 # diss. of Grb2-Sos from receptor, units: /s kp13 2.5e-05 # binding of Shc to receptor (scaled), units: /molecule/s km13 0.6 # diss. of Shc from receptor, units: /s kp15 2.5e-07 # binding of ShcP to receptor (scaled), units: /molecule/s km15 0.3 # diss. of ShcP from receptor, units: /s kp17 1.667e-06 # binding of Grb2 to RP-ShcP (scaled), units: /molecule/s km17 0.1 # diss. of Grb2 from RP-ShcP, units: /s kp18 2.5e-07 # binding of ShcP-Grb2 to receptor (scaled), units: /molecule/s km18 0.3 # diss. of ShcP-Grb2 from receptor, units: /s kp19 5.556e-06 # binding of Sos to RP-ShcP-Grb2 (scaled), units: /molecule/s km19 0.0214 # diss. of Sos from RP-ShcP-Grb2, units: /s kp20 6.667e-08 # binding of ShcP-Grb2-Sos to receptor (scaled), units: /molecule/s km20 0.12 # diss. of ShcP-Grb2-Sos from receptor, units: /s kp24 5e-06 # binding of Grb2-Sos to RP-ShcP (scaled), units: /molecule/s km24 0.0429 # diss. of Grb2-Sos from RP-ShcP, units: /s kp21 1.667e-06 # binding of ShcP to Grb2 in cytosol (scaled), units: /molecule/s km21 0.01 # diss. of Grb2 and SchP in cytosol, units: /s kp23 1.167e-05 # binding of ShcP to Grb2-Sos in cytosol (scaled), units: /molecule/s km23 0.1 # diss. of Grb2-Sos and SchP in cytosol, units: /s kp12 5.556e-08 # binding of Grb2 to Sos in cytosol (scaled), units: /molecule/s km12 0.0015 # diss. of Grb2 and Sos in cytosol, units: /s kp22 1.667e-05 # binding of ShcP-Grb2 to Sos in cytosol (scaled), units: /molecule/s km22 0.064 # diss. of ShcP-Grb2 and Sos in cytosol, units: /s # check detailed balanced loop1 = (kp9/km9)*(kp10/km10)/((kp11/km11)*(kp12/km12)) loop2 = (kp15/km15)*(kp17/km17)/((kp21/km21)*(kp18/km18)) loop3 = (kp18/km18)*(kp19/km19)/((kp22/km22)*(kp20/km20)) loop4 = (kp12/km12)*(kp23/km23)/((kp22/km22)*(kp21/km21)) loop5 = (kp15/km15)*(kp24/km24)/((kp20/km20)*(kp23/km23)) end parameters begin molecule types egf(r) egfr_1(l,r) egfr_2(l,r,Y1068~Y~pY) egfr_3(l,r,Y1148~Y~pY) Grb2(SH2,SH3) Shc(PTB,Y317~Y~pY) Sos(dom) end molecule types begin species egf(r) egf_tot egfr_1(l,r) egfr_tot egfr_2(l,r,Y1068~Y) egfr_tot egfr_3(l,r,Y1148~Y) egfr_tot Grb2(SH2,SH3) Grb2_tot Shc(PTB,Y317~Y) Shc_tot Sos(dom) Sos_tot end species begin observables Molecules Dimers egfr_1(r!1).egfr_2(r!1) Molecules Sos_act Shc(PTB!+,Y317~pY!2).Grb2(SH2!2,SH3!3).Sos(dom!3), egfr_2(Y1068~pY!1).Grb2(SH2!1,SH3!2).Sos(dom!2) Molecules RP egfr_2(Y1068~pY!?), egfr_3(Y1148~pY!?) Molecules Shc_Grb Shc(Y317~pY!1).Grb2(SH2!1) Molecules Shc_Grb_Sos Shc(Y317~pY!1).Grb2(SH2!1,SH3!2).Sos(dom!2) Molecules R_Grb2 egfr_2(Y1068~pY!1).Grb2(SH2!1) Molecules R_Shc egfr_3(Y1148~pY!1).Shc(PTB!1,Y317~Y) Molecules R_ShcP egfr_3(Y1148~pY!1).Shc(PTB!1,Y317~pY!?) Molecules ShcP Shc(Y317~pY!?) Molecules R_G_S egfr_2(Y1068~pY!1).Grb2(SH2!1,SH3!2).Sos(dom!2) # Strong differences are seen for R_G_S in comparison with path model Molecules R_S_G_S egfr_3(Y1148~pY!1).Shc(PTB!1,Y317~pY!2).Grb2(SH2!2,SH3!3).Sos(dom!3) Molecules EGF_tot egf(r), egf(r!1).egfr_1(l!1) # Molecules EGF_free egf(r) Molecules EGF_EGFR_1 egfr_1(l!+,r) end observables begin reaction rules # Ligand-receptor binding egfr_1(l,r) + egf(r) <-> egfr_1(l!1,r).egf(r!1) kp1, km1 #ligand-monomer egfr_2(l,r) <-> egfr_2(l!1,r).egf(r!1) kp1*EGF_free, km1 #ligand-monomer egfr_3(l,r) <-> egfr_3(l!1,r).egf(r!1) kp1*EGF_free, km1 #ligand-monomer # Receptor-aggregation egfr_2(l!+,r) + egfr_1(l!+,r) <-> egfr_2(l!+,r!3).egfr_1(l!+,r!3) kp2, km2 egfr_3(l!+,r) <-> egfr_3(l!+,r!3).egfr_1(l!1,r!3).egf(r!1) kp2*EGF_EGFR_1, km2 # Transphosphorylation of egfr by RTK egfr_2(r!+,Y1068~Y) -> egfr_2(r!+,Y1068~pY) kp3 egfr_3(r!+,Y1148~Y) -> egfr_3(r!+,Y1148~pY) kp3 # Dephosphorylation egfr_2(Y1068~pY) -> egfr_2(Y1068~Y) km3 egfr_3(Y1148~pY) -> egfr_3(Y1148~Y) km3 # Shc transphosph egfr_3(r!+,Y1148~pY!1).Shc(PTB!1,Y317~Y) -> egfr_3(r!+,Y1148~pY!1).Shc(PTB!1,Y317~pY) kp14 Shc(PTB!+,Y317~pY) -> Shc(PTB!+,Y317~Y) km14 # Y1068 activity egfr_2(Y1068~pY) + Grb2(SH2,SH3) <-> egfr_2(Y1068~pY!1).Grb2(SH2!1,SH3) kp9, km9 egfr_2(Y1068~pY) + Grb2(SH2,SH3!+) <-> egfr_2(Y1068~pY!1).Grb2(SH2!1,SH3!+) kp11, km11 egfr_2(Y1068~pY!1).Grb2(SH2!1,SH3) + Sos(dom) <-> egfr_2(Y1068~pY!1).Grb2(SH2!1,SH3!2).Sos(dom!2) kp10, km10 # Y1148 activity egfr_3(Y1148~pY) + Shc(PTB,Y317~Y) <-> egfr_3(Y1148~pY!1).Shc(PTB!1,Y317~Y) kp13, km13 egfr_3(Y1148~pY) + Shc(PTB,Y317~pY) <-> egfr_3(Y1148~pY!1).Shc(PTB!1,Y317~pY) kp15, km15 egfr_3(Y1148~pY) + Shc(PTB,Y317~pY!1).Grb2(SH2!1,SH3) <-> \ egfr_3(Y1148~pY!2).Shc(PTB!2,Y317~pY!1).Grb2(SH2!1,SH3) kp18, km18 egfr_3(Y1148~pY) + Shc(PTB,Y317~pY!1).Grb2(SH2!1,SH3!3).Sos(dom!3) <-> \ egfr_3(Y1148~pY!2).Shc(PTB!2,Y317~pY!1).Grb2(SH2!1,SH3!3).Sos(dom!3) kp20, km20 egfr_3(Y1148~pY!1).Shc(PTB!1,Y317~pY) + Grb2(SH2,SH3) <-> \ egfr_3(Y1148~pY!1).Shc(PTB!1,Y317~pY!2).Grb2(SH2!2,SH3) kp17, km17 egfr_3(Y1148~pY!1).Shc(PTB!1,Y317~pY) + Grb2(SH2,SH3!3).Sos(dom!3) <-> \ egfr_3(Y1148~pY!1).Shc(PTB!1,Y317~pY!2).Grb2(SH2!2,SH3!3).Sos(dom!3) kp24, km24 Shc(PTB!+,Y317~pY!2).Grb2(SH2!2,SH3) + Sos(dom) <-> \ Shc(PTB!+,Y317~pY!2).Grb2(SH2!2,SH3!3).Sos(dom!3) kp19, km19 # Cytosolic Shc(PTB,Y317~pY) + Grb2(SH2,SH3) <-> Shc(PTB,Y317~pY!1).Grb2(SH2!1,SH3) kp21, km21 Shc(PTB,Y317~pY) + Grb2(SH2,SH3!+) <-> Shc(PTB,Y317~pY!1).Grb2(SH2!1,SH3!+) kp23, km23 Shc(PTB,Y317~pY) -> Shc(PTB,Y317~Y) km16 Grb2(SH2,SH3) + Sos(dom) <-> Grb2(SH2,SH3!1).Sos(dom!1) kp12, km12 Shc(PTB,Y317~pY!2).Grb2(SH2!2,SH3) + Sos(dom) <-> \ Shc(PTB,Y317~pY!2).Grb2(SH2!2,SH3!3).Sos(dom!3) kp22, km22 end reaction rules end model ## actions ## # construct reaction network generate_network({overwrite=>1}) # Equilibration #setConcentration("egf(r)",0); #simulate({method=>"ode",t_end=>100000,n_steps=>10,sparse=>1,steady_state=>1}) # Kinetics #setConcentration("egf(r)","egf_tot") #simulate({method=>"ode",t_end=>120,n_steps=>120,atol=>1e-8,rtol=>1e-8,sparse=>1})