def erk_nuclear_initial(fra1=True, elk1=False):
    alias_model_components() 
    if elk1 == True:
        Initial(ELK1(b=None, S383='U'), ELK1_0)
    
    if fra1 == True:
        Initial(FRA1(b=None, st='U'), FRA1_0)

def mapk_initial():

    # Initial conditions obtained from Schoeberl et al.
    Parameter('GAP_0', 1.2e4)
    Parameter('SHC_0', 1.01e6)
    # Parameter('SHCPase_0', 1000)
    Parameter('GRB2_0', 5.1e4)
    Parameter('SOS_0', 6.63e4)
    Parameter('RAS_0', 1.14e7)
    Parameter('RAF_0', 4e4)
    Parameter('MEK_0', 2.2e7)
    Parameter('ERK_0', 2.1e7)
    Parameter('PP1_0', 4e4)
    Parameter('PP2_0', 4e4)
    Parameter('PP3_0', 1e7)

    alias_model_components()

    Initial(GAP(bd=None, b=None), GAP_0)
    Initial(SHC(bgap=None, bgrb=None, batp=None, st='U'), SHC_0)
    Initial(GRB2(b=None, bsos=None), GRB2_0)
    Initial(SOS(bgrb=None, bras=None), SOS_0)
    Initial(RAS(bsos=None, braf=None, st='GDP'), RAS_0)
    Initial(RAF(b=None, st='U'), RAF_0)
    Initial(MEK(b=None, st='U'), MEK_0)
    Initial(ERK(b=None, st='U'), ERK_0)
    Initial(PP1(b=None), PP1_0)
    Initial(PP2(b=None), PP2_0)
    Initial(PP3(b=None), PP3_0)

def albeck_11c(do_pore_transport=True):
    """Model incorporating Bax oligomerization.

    Features:
        - Bid activates Bax
        - Active Bax dimerizes; Bax dimers dimerize to form tetramers
        - Bcl2 binds/inhibits Bax monomers, dimers, and tetramers
        - Bax tetramers bind to and transport Smac to the cytosol
    """

    alias_model_components()
    Initial(Bid(state='U', bf=None), Parameter('Bid_0', 4e4))
    Initial(Bax(bf=None, **inactive_monomer), Parameter('Bax_0', 1e5))
    Initial(Bcl2(bf=None), Parameter('Bcl2_0', 2e4))

    # tBid activates Bax
    catalyze(Bid(state='T'), Bax(inactive_monomer), Bax(active_monomer),
             [1e-7, KR, KC])

    # Bax dimerizes/tetramerizes
    Bax_tetramerizes(bax_active_state='A')

    # Bcl2 inhibits Bax, Bax2, and Bax4
    Bcl2_binds_Bax1_Bax2_and_Bax4(bax_active_state='A')

    if do_pore_transport:
        Initial(Smac(state='M', bf=None), Parameter('Smac_0', 1e6))
        Initial(CytoC(state='M', bf=None), Parameter('CytoC_0', 1e6))
        # NOTE change in KF here from previous model!!!!
        pore_transport(Bax(state='A'), 4, Smac(state='M'), Smac(state='C'),
            [[2*KF, KR, 10]])
        pore_transport(Bax(state='A'), 4, CytoC(state='M'), CytoC(state='C'),
            [[KF, KR, 10]])

def erk_autophos():
    # * How does ERK autophosphorylate?
    # Does an already phosphorylated ERK phosphorylate another one?
    Parameter('kp_erk', 1e-8)
    alias_model_components()
    Rule('ERK_autophos', ERK(b=1, Y='u') % ERK(b=1, Y='p') >>\
                        ERK(b=1, Y='p') % ERK(b=1, Y='p'), kp_erk)

def declare_initial_conditions():
    """Declare initial conditions for Bcl-2 family proteins, Cyto c, and Smac.
    """
    #Parameter('Bid_0'   , 4.0e4) # Bid
    Parameter('BclxL_0' , 2.0e4) # cytosolic BclxL
    Parameter('Mcl1_0'  , 2.0e4) # Mitochondrial Mcl1
    Parameter('Bcl2_0'  , 2.0e4) # Mitochondrial Bcl2
    Parameter('Bad_0'   , 1.0e3) # Bad
    Parameter('Noxa_0'  , 1.0e3) # Noxa
    Parameter('CytoC_0' , 5.0e5) # cytochrome c
    Parameter('Smac_0'  , 1.0e5) # Smac
    Parameter('Bax_0'   , 0.8e5) # Bax
    Parameter('Bak_0'   , 0.2e5) # Bak

    alias_model_components()

    #Initial(Bid(bf=None, state='U'), Bid_0)
    Initial(Bad(bf=None, state='C'), Bad_0)
    Initial(Bax(bf=None, s1=None, s2=None, state='C'), Bax_0)
    Initial(Bak(bf=None, s1=None, s2=None, state='M'), Bak_0)
    Initial(Bcl2(bf=None), Bcl2_0)
    Initial(BclxL (bf=None, state='C'), BclxL_0)
    Initial(Mcl1(bf=None, state='M'), Mcl1_0)
    Initial(Noxa(bf=None, state='C'), Noxa_0)
    Initial(CytoC(bf=None, state='M'), CytoC_0)
    Initial(Smac(bf=None, state='M'), Smac_0)

def effectors_bind_anti_apoptotics():
    alias_model_components()
    """Binding of Bax and Bak to Bcl2, BclxL, and Mcl1.

    Affinities of Bak for Bcl-xL and Mcl-1 are taken from Willis et al.

    Preferential affinity of Bax for Bcl-2 and Bcl-xL were taken from Zhai et
    al.  Bax:Bcl2 and Bax:Bcl-xL affinities were given order of magnitude
    estimates of 10nM.

    See comments on units for :py:func:`tBid_binds_all_anti_apoptotics`.

    Willis, S. N., Chen, L., Dewson, G., Wei, A., Naik, E., Fletcher, J. I.,
    Adams, J. M., et al. (2005). Proapoptotic Bak is sequestered by Mcl-1 and
    Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins. Genes &
    Development, 19(11), 1294-1305. `doi:10.1101/gad.1304105`

    Zhai, D., Jin, C., Huang, Z., Satterthwait, A. C., & Reed, J. C. (2008).
    Differential regulation of Bax and Bak by anti-apoptotic Bcl-2 family
    proteins Bcl-B and Mcl-1. The Journal of biological chemistry, 283(15),
    9580-9586.  `doi:10.1074/jbc.M708426200`
    """

    bind_table([[                            Bcl2,  BclxL(state='M'),         Mcl1],
                [Bax(state='A'), 10e-9*N_A*V,       10e-9*N_A*V,         None],
                [Bak(state='A'),        None,       50e-9*N_A*V,  10e-9*N_A*V]],
               'bf', 'bf', kf=1e6/(N_A*V))

def momp_monomers():
    """Declare the monomers used in the Albeck MOMP modules."""

    # == Activators
    # Bid, states: Untruncated, Truncated, truncated and Mitochondrial
    Monomer('Bid', ['bf', 'state'], {'state':['U', 'T', 'M']})

    # == Effectors
    # Bax, states: Cytoplasmic, Mitochondrial, Active
    # sites 's1' and 's2' are used for pore formation
    Monomer('Bax', ['bf', 's1', 's2', 'state'], {'state':['C', 'M', 'A']})

    # == Anti-Apoptotics
    Monomer('Bcl2', ['bf'])

    # == Cytochrome C and Smac
    Monomer('CytoC', ['bf', 'state'], {'state':['M', 'C', 'A']})
    Monomer('Smac', ['bf', 'state'], {'state':['M', 'C', 'A']})

    alias_model_components()

    # == Annotations
    Annotation(Bid, 'http://identifiers.org/uniprot/P55957')
    Annotation(Bax, 'http://identifiers.org/uniprot/Q07812')
    Annotation(Bcl2, 'http://identifiers.org/uniprot/P10415')
    Annotation(CytoC, 'http://identifiers.org/uniprot/P99999')
    Annotation(Smac, 'http://identifiers.org/uniprot/Q9NR28')

def declare_initial_conditions():
    """Declare initial conditions for Bcl-2 family proteins, Cyto c, and Smac.
        Jurkat Cell parameters were used instead of the Hela cells used in Lopez_modules.
        """
    Parameter('Bid_0'   , 12044) # Bid
    Parameter('BclxL_0' , 36132) # cytosolic BclxL (assigned since Bcl-2 in Jurkats is 36132)
    Parameter('Mcl1_0'  , 36132) # Mitochondrial Mcl1 ("")
    Parameter('Bcl2_0'  , 36132) # Mitochondrial Bcl2
    Parameter('Bad_0'   , 1.0e3) # Bad
    Parameter('Noxa_0'  , 1.0e3) # Noxa
    Parameter('CytoC_0' , 48176) # cytochrome c
    Parameter('Smac_0'  , 48176) # Smac
    Parameter('Bax_0'   , 40145) # Bax
    Parameter('Bak_0'   , 0.2e5) # Bak
    
    alias_model_components()
    
    Initial(Bid(bf=None, state='U'), Bid_0)
    Initial(Bad(bf=None, state='C'), Bad_0)
    Initial(Bax(bf=None, s1=None, s2=None, state='C'), Bax_0)
    Initial(Bak(bf=None, s1=None, s2=None, state='M'), Bak_0)
    Initial(Bcl2(bf=None), Bcl2_0)
    Initial(BclxL (bf=None, state='C'), BclxL_0)
    Initial(Mcl1(bf=None, state='M'), Mcl1_0)
    Initial(Noxa(bf=None, state='C'), Noxa_0)
    Initial(CytoC(bf=None, state='M'), CytoC_0)
    Initial(Smac(bf=None, state='M'), Smac_0)

def mkp_dephos_erk_seq():
    """The parameters are based on Table S2 of Markevich et al. 
    But we assume distributive sequential phosphatase mechanism.

    First and second order rate constants are in s^{-1} and nM^{-1}s^{-1}
    respectively.
    """
    Parameter('kf_mkp', 2.9e-3)    # = h_{-6} + h_{-9}
    Parameter('kf_mkp_p', 1e-2)    # = h_{-3} + h_{7}
    Parameter('kf_mkp_pp', 4.5e-2) # = h_1
    Parameter('kr_mkp', 1.4e-1)    # = h_9 which is also used 
                                   #    in the reaction for the original h_6
    Parameter('kr_mkp_p', 1)       # = h_{3} = h_{-4} = h_{-7} = h_{12}
    Parameter('kr_mkp_pp', 1)      # = h_{-1}
    Parameter('kc_mkp', 5e-1)      # = h_5 which is also used
                                   #    in the reaction for the original h_8
    Parameter('kc_mkp_p', 9.2e-2)  # = h_2
    alias_model_components()

    Rule('MKP_bind_ERK_uu', MKP(b=None) + ERK(b=None, T='u', Y='u') <>\
                            MKP(b=1) % ERK(b=1, T='u', Y='u'), kf_mkp, 
                            kr_mkp)
    Rule('MKP_bind_ERK_pY', MKP(b=None) + ERK(b=None, T='u', Y='p') <>\
                            MKP(b=1) % ERK(b=1, T='u', Y='p'), kf_mkp_p,
                            kr_mkp_p)
    Rule('MKP_bind_ERK_pp', MKP(b=None) + ERK(b=None, T='p', Y='p') <>\
                            MKP(b=1) % ERK(b=1, T='p', Y='p'), 
                            kf_mkp_pp, kr_mkp_pp)

    Rule('MKP_dephos_ERK_ppT', MKP(b=1) % ERK(b=1, T='p', Y='p') >>\
                               MKP(b=None) + ERK(b=None, T='u', Y='p'),
                               kc_mkp_p)
    Rule('MKP_dephos_ERK_pY', MKP(b=1) % ERK(b=1, T='u', Y='p') >>\
                              MKP(b=None) + ERK(b=None, T='u', Y='u'),
                              kc_mkp)

def PI3K_monomers():
    """ Declare monomers in the PI3K arm of the pathway, namely, 
        Gab1, ERK, PI3K, Shp2, PIP2, PIP3, PTEN, Shp, AKT, PDK1 Pase9t, and Pase3
        
        A description of sites on the monomers is given below
        ======================================================
        Gab1 sites: 'atp' is a site to bind ATP
                    'grb2' is a site to bind Grb2
                    'shp2' is a site to bind Shp2
                    'erk' is a site to bind ERK
                    'pase' is a site to bind Pase9t
                    'pi3k' is a site to bind PI3K
                    'state' denotes the phoshorylation status of the species, 
                    with 'up' denoting unphosphorylated,'p' donating singly-phoshorylated and 'pp' denoting doubly phoshporylated
       'gab1' are sites on Shp2, Pase9t, and PI3K to bind Gab1 
       'pip' are sites on AKT, Shp, PTEN, PDK1 to bind PIP3
    """

    Monomer('Gab1',['atp', 'grb2', 'shp2', 'state','erk','pase', 'pi3k'], {'state':['up','p', 'pp']})
    Monomer('Shp2',['gab1'])
    Monomer('Pase_9t', ['gab1'])
    Monomer('PI3K', ['gab1', 'pip2', 'ras'])  # 'pip2' and 'ras' are sites on PI3K to bind PIP2 and RAS
    Monomer('PIP2', ['pi3k']) # 'pi3k' is a site on PIP2 to bind PI3K
    Monomer('PIP3', ['akt', 'pdk','bnd']) # 'akt' and 'pdk' are sites on PIP3 to bind AKT and PDK respectively
    Monomer('AKT', ['pip', 'pase', 'raf', 'state'], {'state':['up','p', 'pp']})
    Monomer('PDK1',['pip'])
    Monomer('Shp', ['pip'])
    Monomer('PTEN', ['pip'])
    Monomer('Pase4', ['akt']) # 'akt' is a site on Pase4 to bind AKT

    alias_model_components()

    global receptors
    receptors = [ErbB1, ErbB2, ErbB3, ErbB4]

def bind_Gab1():
    " v688-694 "
    " Gab1 binds receptor dimers via Grb2 only when (1) dimers are in plasma mem (2) Grb2 (no SOS) is directly bound to receptor "
    
    # Initial amount
    # ==============
    Parameter('Gab1_0',94868.3)     # c426
    # Rate constant
    # ==============
    Parameter('k105', 6.67e-05)         # k105
    Parameter('kd105', 0.1)              # kd105
    Parameter('k122_gab', 1.8704e-8)      # k122
    Parameter('kd122_gab', 1.0)          # kd122
    Parameter('kd123_gab', 0.177828)          # kd123

    alias_model_components()
    
    # Initial conditions
    # ==============
    Initial(Gab1(atp=None, grb2=None, shp2=None, erk=None, pase=None, pi3k=None, state='up'), Gab1_0)
    
    # Rules
    # =====
    for erb in receptors[:2]:
        Rule('Gab1_binds_Grb2_'+erb.name, Gab1(grb2=None,atp=None,shp2=None,erk=None, state='up') +
             Grb2(sos=None, erb=2,gab1=None) % erb(gs=2, comp='pm',cpp=None) <>
             Gab1(grb2=1,atp=None,state='up', erk=None, shp2=None) % Grb2(sos=None, erb=2, gab1=1) % erb(gs=2, comp='pm',cpp=None),
             k105, kd105)

    ## v30-v36, v815-v821
    ## Gab1 + ATP <-> Gab1:ATP -> Gab1~P + ATP
    catalyze(ATP(erb=None), 'gab1', Gab1(state='up',grb2=ANY, shp2=None,erk=None), 'atp', Gab1(state='p',grb2=ANY, shp2=None,erk=None),
             (k122_gab, kd122_gab, kd123_gab))

def bind_PI3K():
    " v621-v627 "
    " PI3K binds scaffolding protein Gab1~P "
    " yet to account for reactions with rc k67, kd67 "
    
    # Initial amount
    # ==============
    Parameter('PI3K_0', 3.55656e+7)    # c287
    # Rate constants
    # ==============
    Parameter('k66', 1.5e-5)   # k66  # K67 and kd67 also used for a subset of rxns, no pattern observed :(
    Parameter('kd66', 0.2)
    Parameter('k67', 5e-5)
    Parameter('kd67', 0.02)

    alias_model_components()
    
    # Initial conditions
    # ==============
    Initial(PI3K(gab1=None, pip2=None, ras=None), PI3K_0)

    # Rules
    # ======
    # This was almost a nice single rule, except a few of the species need a
    # different rate.
    for erb, other_erbs in (ErbB1, receptors), (ErbB2, receptors[1:]):
        for other_erb in other_erbs:
            rates = (k66, kd66)
            if ((erb is ErbB2 and (other_erb is ErbB2 or other_erb is ErbB3)) or
                (erb is ErbB1 and other_erb is ErbB3)):
                rates = (k67, kd67)
            Rule('_'.join((erb.name, other_erb.name, 'bind_gab1_pI3k')),
                 erb() % other_erb() % Gab1(state='p', shp2=None, erk=None, pi3k=None) + PI3K(gab1=None, ras=None, pip2=None) <>
                 erb() % other_erb() % Gab1(state='p', shp2=None, erk=None, pi3k=1) % PI3K(gab1=1, ras=None, pip2=None),
                 *rates)

def cox2_drugs_init(ibuprofen=False):

    if ibuprofen:
        Monomer('IBU', ['b']) #Ibuprofen
        Parameter('IBU_0', 180) #Micromolar
        alias_model_components()
        Initial(IBU(b=None), IBU_0)

def effectors_bind_anti_apoptotics():
    """
    Slightly modified from lopez_modules.embedded version to add that Bcl2 cannot be phosphorylated on S70 and have anti-apoptotic activity. (These interactions turned on in crosstalk modules).    
    Binding of Bax and Bak to Bcl2, BclxL, and Mcl1.

    Affinities of Bak for Bcl-xL and Mcl-1 are taken from Willis et al.

    Preferential affinity of Bax for Bcl-2 and Bcl-xL were taken from Zhai et
    al.  Bax:Bcl2 and Bax:Bcl-xL affinities were given order of magnitude
    estimates of 10nM.

    See comments on units for :py:func:`tBid_binds_all_anti_apoptotics`.

    Willis, S. N., Chen, L., Dewson, G., Wei, A., Naik, E., Fletcher, J. I.,
    Adams, J. M., et al. (2005). Proapoptotic Bak is sequestered by Mcl-1 and
    Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins. Genes &
    Development, 19(11), 1294-1305. `doi:10.1101/gad.1304105`

    Zhai, D., Jin, C., Huang, Z., Satterthwait, A. C., & Reed, J. C. (2008).
    Differential regulation of Bax and Bak by anti-apoptotic Bcl-2 family
    proteins Bcl-B and Mcl-1. The Journal of biological chemistry, 283(15),
    9580-9586.  `doi:10.1074/jbc.M708426200`
    """

    alias_model_components()
    bind_table([[                            Bcl2(S70='U'),  BclxL(state='M'),         Mcl1],
                [Bax(active_monomer), 10e-9*N_A*V,       10e-9*N_A*V,         None],
                [Bak(active_monomer),        None,       50e-9*N_A*V,  10e-9*N_A*V]],
               kf=1e6/(N_A*V))

def rec_events_inh_ERL():
    """Receptor events involving the EGFR kinase inhibitor erlotinib.  Binds in the ATP binding pocket."""
    alias_model_components()
    
    #Binding of erlotinib to EGFR
    #Assumption here: erlotinib only binds to dimers and its ligand binding status doesn't matter (need to check this)
    bind(erbb(ty='1', bd=ANY, st='U', loc='C'), 'b', ERL(), 'b', par['EGFR_bind_ERL'])    

def tsc2_gap_function():
    """GTPase Activating Protein activity of TSC2 on Rheb GTPase.
    References:
    Huang, J. & Manning, B. D. The TSC1-TSC2 complex: a molecular switchboard controlling cell growth. Biochem J 412, 179–190 (2008).
    """
    
    alias_model_components()
    # TSC2 can bind Rheb, inhibiting its GTPase activity if TSC2 is phosphorylated on S664 or S1798 (if phosphorylated on S939, S981, or T1462, TSC2 translocates from the membrane to the cytosol and can't bind Rheb at all).
    bind(TSC(S939='U', S981='U', T1462='U'), 'b', Rheb(S='GTP', bmTOR=None), 'bTSC', par['TSC2_bind_Rheb'])

    Rule('TSC2_Rheb',
         TSC(b=1, S1387='U', S664='U', S1798='U') % Rheb(S='GTP', bTSC=1, bmTOR=None) >>
         TSC(b=1, S1387='U', S664='U', S1798='U') % Rheb(S='GDP', bTSC=1, bmTOR=None),
         par['TSC2_Rheb_GTPase'])
    
    for site in ['S664', 'S1798']:
        Rule('TSC2_'+site+'_Rheb',
             TSC({'b':1, site:'P'}) % Rheb(S='GTP', bTSC=1, bmTOR=None) >>
             TSC({'b':1, site:'P'}) % Rheb(S='GDP', bTSC=1, bmTOR=None),
             par['TSC2p_Rheb_GTPase'])

    # If TSC2 is phosphorylated on S1387, its GAP activity is increased.
    Rule('TSC2_S1387_Rheb',
         TSC(b=1, S1387='P') % Rheb(S='GTP', bTSC=1, bmTOR=None) >>
         TSC(b=1, S1387='P') % Rheb(S='GDP', bTSC=1, bmTOR=None),
         par['TSC2pS1387_Rheb_GTPase'])

def receptor_dimerization():
    """ ErbB receptor dimerization. 
    """
    
    # ErbB dimerization
    # ErbB1 is not required to contain a ligand in order to dimerize (3 and 4 are)
    # Rates for ErbB1 dimerization with and without ligand are different
    # Assumptions: 
    # ErbB3/ErbB3 and ErbB3/ErbB4 dimers neglected (assumed to be at very low concentration since both components likely are)
    # ErbB3 and ErbB4 have the same dimerization rate independent of ligand
    # If we ever add multiple ligand types per receptor, the rates for dimerization as defined currently will not depend on the ligand type
    # These rules only cover binding/unbinding of unphosphorylated receptors.  Binding/unbinding of phosphorylated receptors is currently in ErbB2 lateral signaling section 
    
    alias_model_components()    
    
    erbb1 = erbb(ty='1', bl=None, b=None, st='U', loc='C')
    erbb1Lig = erbb(ty='1', bl=ANY, b=None, st='U', loc='C')
    erbb2Lig = erbb(ty='2', b=None, st='U', loc='C')
    erbb3Lig = erbb(ty='3', b=None, st='U', loc='C', pi3k1=None, pi3k2=None, pi3k3=None, pi3k4=None, pi3k5=None, pi3k6=None)
    erbb4Lig = erbb(ty='4', b=None, st='U', loc='C')
    bind_table([[                          erbb1,                      erbb1Lig,                     erbb2Lig,                    erbb3Lig, erbb4Lig],
                [erbb1,                    (par['ErbB1_bind_ErbB1']),  None,                         None,                        None,     None],
                [erbb1Lig,                 (par['ErbB1_bind_ErbB1L']), (par['ErbB1L_bind_ErbB1L']),  None,                        None,     None],
                [erbb2Lig,                 (par['ErbB1_bind_ErbB2']),  (par['ErbB1L_bind_ErbB2']),   (par['ErbB2_bind_ErbB2']),   None,     None],
                [erbb3Lig,                 (par['ErbB1_bind_ErbB3']),  (par['ErbB1L_bind_ErbB3']),   (par['ErbB2_bind_ErbB3']),   None,     None],
                [erbb4Lig,                 (par['ErbB1_bind_ErbB4']),  (par['ErbB1L_bind_ErbB4']),   (par['ErbB2_bind_ErbB4']),   None,     None]],
                'bd', 'bd')

def embedded(do_pore_transport=True):
    """ Direct and indirect modes of action, occurring at the membrane.
    """
    alias_model_components()

    declare_initial_conditions()

    translocate_tBid_Bax_BclxL()

    tBid_activates_Bax_and_Bak()


    # Autoactivation: Bax and Bak activate their own kind, but only when
    # free (i.e. not part of a pore complex)
    catalyze(Bax(active_monomer), Bax(state='M'), Bax(state='A'),
             activation_rates)
    catalyze(Bak(active_monomer), Bak(state='M'), Bak(state='A'),
             activation_rates)

    # Anti-apoptotics bind activator tBid
    # Doug Green's "MODE 1" inhibition
    tBid_binds_all_anti_apoptotics()

    # Anti-apoptotics bind activated effectors
    # Doug Green's "MODE 2" inhibition
    effectors_bind_anti_apoptotics()

    sensitizers_bind_anti_apoptotics()

    # Bax and Bak form pores by sequential addition and transport CytoC/Smac
    lopez_pore_formation(do_pore_transport=do_pore_transport)

def ligand_to_c8_monomers():
    """ Declares ligand, receptor, DISC, Flip, Bar and Caspase 8.

    'bf' is the site to be used for all binding reactions.

    The 'state' site denotes various localization and/or activity states of a
    Monomer, with 'C' denoting cytoplasmic localization and 'M' mitochondrial
    localization.
    """

    Monomer('L', ['bf']) # Ligand
    Monomer('R', ['bf']) # Receptor
    Monomer('DISC', ['bf']) # Death-Inducing Signaling Complex
    Monomer('flip', ['bf'])
    # Caspase 8, states: pro, Active
    Monomer('C8', ['bf', 'state'], {'state':['pro', 'A']})
    Monomer('BAR', ['bf'])

    alias_model_components()

    # == Annotations
    Annotation(L, 'http://identifiers.org/uniprot/P50591')
    Annotation(R, 'http://identifiers.org/uniprot/O14763')
    Annotation(DISC, 'http://identifiers.org/obo.go/GO:0031264')
    Annotation(flip, 'http://identifiers.org/uniprot/O15519')
    Annotation(C8, 'http://identifiers.org/uniprot/Q14790')
    Annotation(BAR, 'http://identifiers.org/uniprot/Q9NZS9')

def indirect(do_pore_transport=True):
    """Bax and Bak spontaneously form pores without activation.
       The "activator" tBid binds all of the anti-apoptotics.
    """
    alias_model_components()

    declare_initial_conditions()

    translocate_tBid_Bax_BclxL()

    # Bax and Bak spontaneously become activated
    free_Bax = Bax(bf=None, s1=None, s2=None) # Alias
    free_Bak = Bak(bf=None, s1=None, s2=None) # Alias
    equilibrate(free_Bax(state='M'), free_Bax(state='A'), transloc_rates)
    equilibrate(free_Bak(state='M'), free_Bak(state='A'), transloc_rates)

    # Anti-apoptotics bind activator tBid
    # Doug Green's "MODE 1" inhibition
    tBid_binds_all_anti_apoptotics()

    # Anti-apoptotics bind activated effectors
    # Doug Green's "MODE 2" inhibition
    effectors_bind_anti_apoptotics()

    sensitizers_bind_anti_apoptotics()

    # Bax and Bak form pores by sequential addition
    lopez_pore_formation(do_pore_transport=do_pore_transport)