# This is a demo model of EGFR signaling. # The parameters and rules have been modified to keep things # as simple as possible. begin model begin parameters NA 6.02e23 # Avogadro's number (molecues/mol) f 0.01 # Fraction of the cell to simulate Vo f*1.0e-10 # Extracellular volume=1/cell_density (L) V f*3.0e-12 # Cytoplasmic volume (L) # Inital amount of ligand (nM) EGF_init 20*1e-10*NA*Vo # convert to copies per cell # Initial amounts of cellular components (copies per cell) EGFR_init f*1.8e5 Grb2_init f*1.5e5 Sos1_init f*6.2e4 # Rate constants # Divide by NA*Vcyt to convert bimolecular rate constants # from /M/sec to /(molecule/cell)/sec kp1 3.0e6/(NA*V) # ligand-monomer binding km1 0.06 # ligand-monomer dissociation kp2 1.0e7/(NA*V) # aggregation of bound monomers km2 0.1 # dissociation of bound monomers kp3 0.5 # dimer transphosphorylation km3 4.505 # dimer dephosphorylation kp4 1.5e6/(NA*V) # binding of Grb2 to receptor km4 0.05 # dissociation of Grb2 from receptor kp5 1.0e7/(NA*V) # binding of Grb2 to Sos1 km5 0.06 # dissociation of Grb2 from Sos1 deg 0.01 # degradation of receptor dimers end parameters begin molecule types EGF(R) EGFR(L,CR1,Y1068~U~P) Grb2(SH2,SH3) Sos1(PxxP) Null() end molecule types begin seed species # Convert EGF conc. from nM to molecule/cell EGF(R) 0 EGFR(L,CR1,Y1068~U) EGFR_init Grb2(SH2,SH3) Grb2_init Sos1(PxxP) Sos1_init end seed species begin observables Molecules Sos1_act EGFR(Y1068!1).Grb2(SH2!1,SH3!2).Sos1(PxxP!2) Molecules EGFR_tot EGFR() Molecules Lig_free EGF(R) Species Dim EGFR(CR1!+) Molecules RP EGFR(Y1068~P!?) # Cytosolic Grb2-Sos1 Molecules Grb2Sos1 Grb2(SH2,SH3!1).Sos1(PxxP!1) end observables begin reaction rules # Ligand-receptor binding R1: EGFR(L,CR1) + EGF(R) <-> EGFR(L!1,CR1).EGF(R!1) kp1, km1 # Receptor-aggregation R2: EGFR(L!+,CR1) + EGFR(L!+,CR1) <-> EGFR(L!+,CR1!1).EGFR(L!+,CR1!1) kp2,km2 # Transphosphorylation of EGFR by RTK R3: EGFR(CR1!+,Y1068~U) -> EGFR(CR1!+,Y1068~P) kp3 # Dephosphorylation R4: EGFR(Y1068~P) -> EGFR(Y1068~U) km3 # Grb2 binding to pY1068 R5: EGFR(Y1068~P) + Grb2(SH2) <-> EGFR(Y1068~P!1).Grb2(SH2!1) kp4,km4 # Grb2 binding to Sos1 R6: Grb2(SH3) + Sos1(PxxP) <-> Grb2(SH3!1).Sos1(PxxP!1) kp5,km5 # Receptor dimer internalization/degradation #R7: EGF(R!1).EGF(R!2).EGFR(L!1,CR1!3).EGFR(L!2,CR1!3) -> Null() deg DeleteMolecules end reaction rules end model begin actions #writeXML({suffix=>"bngxml"}) generate_network({overwrite=>1}) # Equilibration #simulate({method=>ode,suffix=>equil,t_end=>100000,n_steps=>10,sparse=>1,steady_state=>1}) # Kinetics #setConcentration("EGF(R)","EGF_init") #simulate({method=>"ode",t_start=>0,t_end=>100,n_steps=>40}) #setConcentration("EGF(R)", "10*EGF_init") #simulate({method=>"ode",t_end=>200,n_steps=>40,continue=>1}) #setConcentration("EGF(R)", "0.1*EGF_init") #simulate({method=>"ode",t_end=>300,n_steps=>40,continue=>1}) #resetConcentrations() # reverts to saved Concentrations # Stochastic simulation #setConcentration("EGF(R)","EGF_init") #simulate({method=>"ssa",suffix=>"ssa",t_start=>0,t_end=>100,n_steps=>40}) #setConcentration("EGF(R)", "10*EGF_init") #simulate({method=>"ssa",suffix=>"ssa",t_end=>200,n_steps=>40,continue=>1}) #setConcentration("EGF(R)", "0.1*EGF_init") #simulate({method=>"ssa",suffix=>"ssa",t_end=>300,n_steps=>40,continue=>1}) end actions