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nfkb.bngl
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#Reduced model
begin model
begin molecule types
TNFR(st~a~i) # active/inactive TNFR1 receptors
TNF()
ikk(s~N~A) #IKK is active/neutral
ikba(loc~c~n,nfkb) # ikba is found in the cytoplasm/nucleus, and has a binding site for nfkb
nfkb(loc~c~n,ikba) # nfkb is found in the cytoplasm/nucleus, and has a binding site for IkB
A20()
end molecule types
begin parameters
Tot_NFKB log10(1e4) #Total protein concentration of NFkB, molecules
IKK_N log10(2e4) #Total protein concentration of IKK, molecules
R log10(7000) #Total protein concentration or receptor, molecules
######################################
# Reactions from Pekalski et al. (Lipniacki)
#c_deg log10(2e-4)
k_b log10(1.2e-5) #L #0.0352 # TNF-TNFR activation rate, per molecule per second
k_f log10(1.2e-3) #L #TNFR inactivation rate, per second
k_a -4.5164 #TNFR mediated IKK activation rate, per molecule per second
k_4 log10(1e-3)#L #IKK inactivation rate, per second
# Simplified reactions from Lee at al (Fold Change paper)
ka1a = log10(5e-7)#L #IkB-NFkB binding rate, per molecule per second
kd1a = -8 # IkB-NFkB unbinding rate, per second
ki1 = -2.057 # NFkB entry into the nucleus, per second
ke1 = -5.9334 # NFkB exit from the nucleus, per second
ki2 = -4.1089 #IkB entry into the nucleus, per second
ke2 = -10.6289 #IkB exit from the nucleus, per second
ke2a = -3.5859 #IkB-NFkB complex exit from nuclues, per second
c4a = -4.6363 #Basal degradation of free cytoplasmic IkB, per second
c5a = -4.6 #Basal degradation of bound cytoplasmic IkB, per second
kt1a = -7.3178 ##IKK mediated degradation of free cytoplasmic IkB, per molecule second
kt2a = -8 #IKK mediated degradation of bound cytoplasmic IkB, per molecule per second
c1a = -3.2082 #NFkB mediated production of free cytoplasmic IkB
end parameters
begin observables
Molecules nNFKB nfkb(loc~n,ikba)>=10 #nuclear free nfkb
Molecules cNFKB nfkb(loc~c,ikba) #cytoplasmic free nfkb
Molecules cikba {MatchOnce}ikba(loc~c,nfkb) #cytoplasmic free ikba
Species Ccomplex nfkb(loc~c,ikba!1).ikba(loc~c,nfkb!1) #cytoplasmic ikba-nfkb complex
Molecules nikba ikba(loc~n,nfkb) #nuclear free ikba
Species ncomplex nfkb(loc~n,ikba!1).ikba(loc~n,nfkb!1) #nuclear ikba-nfkb complex
Molecules ikkN ikk(s~N) #neutral ikk
Molecules ikka ikk(s~A) #activated ikk
Molecules TNFR_a TNFR(st~a) #active TNFR
Molecules TNFR_i TNFR(st~i) #inactive TNFR
label: Molecules TNF TNF() #TNF
end observables
begin seed species
nfkb(loc~n,ikba) 0 #nuclear free nfkb
nfkb(loc~c,ikba) 0 #cytoplasmic free nfkb
0 @t%tag:$ikba(loc~c,nfkb).B(loc) 0 #cytoplasmic free ikba
label: @C:$nfkb(loc~c,ikba!1).ikba(loc~c,nfkb!1) 10^Tot_NFKB #cytoplasmic ikba-nfkb complex
$ikba(loc~n,nfkb) 0 #nuclear free ikba
nfkb(loc~n,ikba!1).ikba(loc~n,nfkb!1) 0 #nuclear ikba-nfkb complex
ikk(s~N)@comp 10^IKK_N #neutral ikk
_test: ikk(s~A)%tag 0 #activated ikk
TNFR(st~a) 0 #active TNFR
TNFR(st~i) 10^R #inactive TNFR
TNF() 0 #TNF
end seed species
begin reaction rules
R1_TNF_degradation: TNF() -> 0 0
R2_TNFR_activation: TNFR(st~i) + TNF() -> {MatchOnce}TNFR(st~a) + TNF() (10^k_b)
R3_TNFR_inactivation: TNFR(st~a) -> TNFR(st~i) (10^k_f)
R4_ikk_activation: ikk(s~N) +TNFR(st~a) -> ikk(s~A)+TNFR(st~a) (10^k_a)
R5_ikk_inactivation: ikk(s~A) -> ikk(s~N) 10^k_4
R6_reversible_cytoplasmic_complex_formation: ikba(loc~c,nfkb) + nfkb(loc~c,ikba) <-> ikba(loc~c,nfkb!1).nfkb(loc~c,ikba!1) 10^(ka1a),10^kd1a
R7_reversible_nuclear_complex_formation: nfkb(loc~n,ikba) + ikba(loc~n,nfkb) <-> nfkb(loc~n,ikba!1).ikba(loc~n,nfkb!1) 3.3*(10^ka1a),10^kd1a
R8_ikk_mediated_cytoplasmic_free_ikb_degradation: ikk(s~A)+ikba(loc~c,nfkb) -> ikk(s~A) 10^kt1a
R9_ikk_mediated_cytoplasmic_bound_ikb_degradation: ikk(s~A)+nfkb(loc~c,ikba!1).ikba(loc~c,nfkb!1) ->ikk(s~A)+ nfkb(loc~c,ikba) 10^kt2a
R10_basal_cytoplasmic_free_ikb_degradation: ikba(loc~c,nfkb) -> 0 10^c4a
R11_basal_cytoplasmic_bound_ikb_degradation: nfkb(loc~c,ikba!1).ikba(loc~c,nfkb!1) -> nfkb(loc~c,ikba) 10^c5a
R12_nfkb_shuttling: nfkb(loc~c,ikba) <-> nfkb(loc~n,ikba) (10^ki1),(10^ke1)
R13_ikb_shuttling: ikba(loc~c,nfkb) <-> ikba(loc~n,nfkb) (10^ki2),(10^ke2)
R14_ikb_linear_transcription: nfkb(loc~n,ikba) -> nfkb(loc~n,ikba) + ikba(loc~c,nfkb) 10^c1a
R15_export_nuclearcomplex: ikba(loc~n,nfkb!1).nfkb(loc~n,ikba!1) -> ikba(loc~c,nfkb!1).nfkb(loc~c,ikba!1) 10^ke2a
end reaction rules
end model
generate_network({overwrite=>1})
#writeMfile({})
writeMexfile({})
#Equilibration
simulate_ode({t_start=>0,t_end=>1e8,n_steps=>1000,atol=>1.0E-6,rtol=>1.0E-8})
#Simulate
setConcentration("TNF()",5)
simulate_ode({t_start=>0,t_end=>300,n_steps=>300})
setConcentration("TNF()",0)
simulate_ode({t_end=>14100,continue=>1, n_steps=>1000})