/* * Temporal self-organization of the cyclin/Cdk network driving * the mammalian cell cycle * * Model Status * * This CellML model runs in OpenCell and COR. It was created from * equations [1] to [46]. The model parameters were taken from * the Parameters document. The units have been checked and they * are consistent. v_sw has been set to 0 in this particular model * which means the model is de-coupled from the circadian clock. * The CellML model runs to replicate the first part of figure * 7B. * * Model Structure * * We propose an integrated computational model for the network * of cyclin-dependent kinases (Cdks) that controls the dynamics * of the mammalian cell cycle. The model contains four Cdk modules * regulated by reversible phosphorylation, Cdk inhibitors, and * protein synthesis or degradation. Growth factors (GFs) trigger * the transition from a quiescent, stable steady state to self-sustained * oscillations in the Cdk network. These oscillations correspond * to the repetitive, transient activation of cyclin D/Cdk4-6 in * G(1), cyclin E/Cdk2 at the G(1)/S transition, cyclin A/Cdk2 * in S and at the S/G(2) transition, and cyclin B/Cdk1 at the * G(2)/M transition. The model accounts for the following major * properties of the mammalian cell cycle: (i) repetitive cell * cycling in the presence of suprathreshold amounts of GF; (ii) * control of cell-cycle progression by the balance between antagonistic * effects of the tumor suppressor retinoblastoma protein (pRB) * and the transcription factor E2F; and (iii) existence of a restriction * point in G(1), beyond which completion of the cell cycle becomes * independent of GF. The model also accounts for endoreplication. * Incorporating the DNA replication checkpoint mediated by kinases * ATR and Chk1 slows down the dynamics of the cell cycle without * altering its oscillatory nature and leads to better separation * of the S and M phases. The model for the mammalian cell cycle * shows how the regulatory structure of the Cdk network results * in its temporal self-organization, leading to the repetitive, * sequential activation of the four Cdk modules that brings about * the orderly progression along cell-cycle phases. * * The original paper reference is cited below: * * Temporal self-organization of the cyclin/Cdk network driving * the mammalian cell cycle. Goldbeter A, Gerard C, 2009, Unite * de Chronobiologie Theorique, 106(51), 21643-8. PubMed ID: 20007375 * * reaction diagram * * [[Image file: gerard_2009.png]] * * GF-induced oscillations in the Cdk network. (A) Below a sharp * threshold in the concentration of GF, the Cdk network evolves * to a stable steady state, whereas sustained oscillations occur * above the threshold that corresponds to a bifurcation beyond * which the steady state becomes unstable */ import nsrunit; unit conversion on; // unit micromolar predefined // unit nanomolar predefined unit hour=3600 second^1; unit first_order_rate_constant=2.7777778E-4 second^(-1); unit flux=2.7777778E-7 meter^(-3)*second^(-1)*mole^1; unit second_order_rate_constant=.27777778 meter^3*second^(-1)*mole^(-1); unit per_micromolar=1E3 meter^3*mole^(-1); unit nano_flux=2.7777778E-10 meter^(-3)*second^(-1)*mole^1; unit first_order_rate_constant_nano=2.7777778E-4 second^(-1); unit second_order_rate_constant_nano=2.7777778E2 meter^3*second^(-1)*mole^(-1); math main { realDomain time hour; time.min=0; extern time.max; extern time.delta; real AP1(time) micromolar; when(time=time.min) AP1=0.01; real v_sap1 flux; v_sap1=1; real GF micromolar; GF=1; real K_agf micromolar; K_agf=0.1; real k_dap1 first_order_rate_constant; k_dap1=0.15; real eps dimensionless; eps=17; real pRB(time) micromolar; when(time=time.min) pRB=1; real v_sprb flux; v_sprb=0.8; real k_pc1 second_order_rate_constant; k_pc1=0.05; real E2F(time) micromolar; when(time=time.min) E2F=0.01; real k_pc2 first_order_rate_constant; k_pc2=0.5; real pRBc1(time) micromolar; when(time=time.min) pRBc1=0.1; real V_1 first_order_rate_constant; V_1=2.2; real K_1 micromolar; K_1=0.1; real Md(time) micromolar; when(time=time.min) Md=0.01; real Mdp27(time) micromolar; when(time=time.min) Mdp27=0.01; real V_2 flux; V_2=2; real pRBp(time) micromolar; when(time=time.min) pRBp=0.25; real K_2 micromolar; K_2=0.1; real k_dprb first_order_rate_constant; k_dprb=0.01; real V_3 first_order_rate_constant; V_3=1; real K_3 micromolar; K_3=0.1; real Me(time) micromolar; when(time=time.min) Me=0.01; real V_4 flux; V_4=2; real pRBpp(time) micromolar; when(time=time.min) pRBpp=0.1; real K_4 micromolar; K_4=0.1; real k_pc3 second_order_rate_constant; k_pc3=0.025; real k_pc4 first_order_rate_constant; k_pc4=0.5; real pRBc2(time) micromolar; when(time=time.min) pRBc2=0.05; real k_dpRBp first_order_rate_constant; k_dpRBp=0.06; real k_dpRBpp first_order_rate_constant; k_dpRBpp=0.04; real v_se2f flux; v_se2f=0.17; real V_1e2f first_order_rate_constant; V_1e2f=4; real Ma(time) micromolar; when(time=time.min) Ma=0.01; real K_1e2f micromolar; K_1e2f=5; real V_2e2f flux; V_2e2f=0.75; real E2Fp(time) micromolar; when(time=time.min) E2Fp=0.01; real K_2e2f micromolar; K_2e2f=5; real k_de2f first_order_rate_constant; k_de2f=0.002; real k_de2fp first_order_rate_constant; k_de2fp=1.1; real Cd(time) micromolar; when(time=time.min) Cd=0.01; real k_cd1 first_order_rate_constant; k_cd1=0.4; real k_cd2 first_order_rate_constant; k_cd2=0.005; real K_i7 micromolar; K_i7=0.1; real K_i8 micromolar; K_i8=2; real k_com1 second_order_rate_constant; k_com1=0.175; real Cdk4_tot micromolar; Cdk4_tot=1.5; real Mdi(time) micromolar; when(time=time.min) Mdi=0.01; real k_decom1 first_order_rate_constant; k_decom1=0.1; real V_dd flux; V_dd=5; real K_dd micromolar; K_dd=0.1; real k_ddd first_order_rate_constant; k_ddd=0.005; real V_m2d flux; V_m2d=0.2; real K_2d micromolar; K_2d=0.1; real V_m1d flux; V_m1d=1; real K_1d micromolar; K_1d=0.1; real k_c1 second_order_rate_constant; k_c1=0.15; real p27(time) micromolar; when(time=time.min) p27=0.01; real k_c2 first_order_rate_constant; k_c2=0.05; real Ce(time) micromolar; when(time=time.min) Ce=0.01; real k_ce first_order_rate_constant; k_ce=0.29; real K_i9 micromolar; K_i9=0.1; real K_i10 micromolar; K_i10=2; real k_com2 second_order_rate_constant; k_com2=0.2; real Cdk2_tot micromolar; Cdk2_tot=2; real Mei(time) micromolar; when(time=time.min) Mei=0.01; real Mep27(time) micromolar; when(time=time.min) Mep27=0.01; real Mai(time) micromolar; when(time=time.min) Mai=0.01; real Map27(time) micromolar; when(time=time.min) Map27=0.01; real k_decom2 first_order_rate_constant; k_decom2=0.1; real V_de flux; V_de=3; real Skp2(time) micromolar; when(time=time.min) Skp2=0.01; real K_dceskp2 micromolar; K_dceskp2=2; real K_de micromolar; K_de=0.1; real k_dde first_order_rate_constant; k_dde=0.005; real V_m2e first_order_rate_constant; V_m2e=1.4; real Wee1(time) micromolar; when(time=time.min) Wee1=0.1; real i_b1 micromolar; i_b1=0.5; real K_2e micromolar; K_2e=0.1; real V_m1e first_order_rate_constant; V_m1e=2; real Pe(time) micromolar; when(time=time.min) Pe=0.01; real K_1e micromolar; K_1e=0.1; real k_c3 second_order_rate_constant; k_c3=0.2; real k_c4 first_order_rate_constant; k_c4=0.1; real v_sskp2 flux; v_sskp2=0.15; real V_dskp2 flux; V_dskp2=1.1; real K_dskp2 micromolar; K_dskp2=0.5; real Cdh1a(time) micromolar; when(time=time.min) Cdh1a=0.01; real K_cdh1 micromolar; K_cdh1=0.4; real k_ddskp2 first_order_rate_constant; k_ddskp2=0.005; real Pei(time) micromolar; when(time=time.min) Pei=0.01; real v_spei flux; v_spei=0.13; real V_6e flux; V_6e=0.8; real x_e1 dimensionless; x_e1=1; real x_e2 per_micromolar; x_e2=1; real Chk1(time) micromolar; when(time=time.min) Chk1=0.01; real K_6e micromolar; K_6e=0.1; real V_m5e first_order_rate_constant; V_m5e=5; real a_e micromolar; a_e=0.25; real K_5e micromolar; K_5e=0.1; real k_dpei first_order_rate_constant; k_dpei=0.15; real k_dpe first_order_rate_constant; k_dpe=0.075; real Ca(time) micromolar; when(time=time.min) Ca=0.01; real k_ca first_order_rate_constant; k_ca=0.0375; real K_i11 micromolar; K_i11=0.1; real K_i12 micromolar; K_i12=2; real k_com3 second_order_rate_constant; k_com3=0.2; real k_decom3 first_order_rate_constant; k_decom3=0.1; real V_da flux; V_da=2.5; real K_da micromolar; K_da=1.1; real Cdc20a(time) micromolar; when(time=time.min) Cdc20a=0.01; real K_acdc20 micromolar; K_acdc20=2; real k_dda first_order_rate_constant; k_dda=0.005; real V_m2a first_order_rate_constant; V_m2a=1.85; real i_b2 micromolar; i_b2=0.5; real K_2a micromolar; K_2a=0.1; real V_m1a first_order_rate_constant; V_m1a=2; real Pa(time) micromolar; when(time=time.min) Pa=0.01; real K_1a micromolar; K_1a=0.1; real k_c5 second_order_rate_constant; k_c5=0.15; real k_c6 first_order_rate_constant; k_c6=0.125; real v_s1p27 flux; v_s1p27=0.8; real v_s2p27 first_order_rate_constant; v_s2p27=0.1; real K_i13 micromolar; K_i13=0.1; real K_i14 micromolar; K_i14=2; real k_c7 second_order_rate_constant; k_c7=0.12; real Mb(time) micromolar; when(time=time.min) Mb=0.01; real k_c8 first_order_rate_constant; k_c8=0.2; real Mbp27(time) micromolar; when(time=time.min) Mbp27=0.01; real V_1p27 first_order_rate_constant; V_1p27=100; real K_1p27 micromolar; K_1p27=0.5; real V_2p27 flux; V_2p27=0.1; real K_2p27 micromolar; K_2p27=0.5; real p27p(time) micromolar; when(time=time.min) p27p=0.01; real k_ddp27 first_order_rate_constant; k_ddp27=0.06; real V_dp27p flux; V_dp27p=5; real K_dp27skp2 micromolar; K_dp27skp2=0.1; real K_dp27p micromolar; K_dp27p=0.1; real k_ddp27p first_order_rate_constant; k_ddp27p=0.01; real Cdh1i(time) micromolar; when(time=time.min) Cdh1i=0.01; real V_2cdh1 first_order_rate_constant; V_2cdh1=8; real K_2cdh1 micromolar; K_2cdh1=0.01; real V_1cdh1 flux; V_1cdh1=1.25; real K_1cdh1 micromolar; K_1cdh1=0.01; real k_dcdh1i first_order_rate_constant; k_dcdh1i=0.2; real v_scdh1a flux; v_scdh1a=0.11; real k_dcdh1a first_order_rate_constant; k_dcdh1a=0.1; real Pai(time) micromolar; when(time=time.min) Pai=0.01; real v_spai flux; v_spai=0.105; real V_6a flux; V_6a=1; real x_a1 dimensionless; x_a1=1; real x_a2 per_micromolar; x_a2=1; real K_6a micromolar; K_6a=0.1; real V_m5a first_order_rate_constant; V_m5a=4; real a_a micromolar; a_a=0.2; real K_5a micromolar; K_5a=0.1; real k_dpai first_order_rate_constant; k_dpai=0.15; real k_dpa first_order_rate_constant; k_dpa=0.075; real Cb(time) micromolar; when(time=time.min) Cb=0.01; real v_cb flux; v_cb=0.05; real k_com4 second_order_rate_constant; k_com4=0.25; real Cdk1_tot micromolar; Cdk1_tot=0.5; real Mbi(time) micromolar; when(time=time.min) Mbi=0.01; real k_decom4 first_order_rate_constant; k_decom4=0.1; real V_db flux; V_db=0.06; real K_db micromolar; K_db=0.005; real K_dbcdc20 micromolar; K_dbcdc20=0.2; real K_dbcdh1 micromolar; K_dbcdh1=0.1; real k_ddb first_order_rate_constant; k_ddb=0.005; real V_m2b first_order_rate_constant; V_m2b=2.1; real i_b3 micromolar; i_b3=0.5; real K_2b micromolar; K_2b=0.1; real V_m1b first_order_rate_constant; V_m1b=3.9; real Pb(time) micromolar; when(time=time.min) Pb=0.01; real K_1b micromolar; K_1b=0.1; real Cdc20i(time) micromolar; when(time=time.min) Cdc20i=0.01; real v_scdc20i flux; v_scdc20i=0.1; real V_m3b first_order_rate_constant; V_m3b=8; real K_3b micromolar; K_3b=0.1; real V_m4b flux; V_m4b=0.7; real K_4b micromolar; K_4b=0.1; real k_dcdc20i first_order_rate_constant; k_dcdc20i=0.14; real k_dcdc20a first_order_rate_constant; k_dcdc20a=0.05; real Pbi(time) micromolar; when(time=time.min) Pbi=0.01; real v_spbi flux; v_spbi=0.12; real V_6b flux; V_6b=1; real x_b1 dimensionless; x_b1=1; real x_b2 per_micromolar; x_b2=1; real K_6b micromolar; K_6b=0.1; real V_m5b first_order_rate_constant; V_m5b=5; real a_b micromolar; a_b=0.11; real K_5b micromolar; K_5b=0.1; real k_dpbi first_order_rate_constant; k_dpbi=0.2; real k_dpb first_order_rate_constant; k_dpb=0.1; real v_swee1 flux; v_swee1=0.06; real k_sw first_order_rate_constant; k_sw=5; real Mw(time) micromolar; when(time=time.min) Mw=0; real V_m7b first_order_rate_constant; V_m7b=1.2; real i_b micromolar; i_b=0.75; real K_7b micromolar; K_7b=0.1; real V_m8b flux; V_m8b=1; real Wee1p(time) micromolar; when(time=time.min) Wee1p=0.01; real K_8b micromolar; K_8b=0.1; real k_dwee1 first_order_rate_constant; k_dwee1=0.1; real k_dwee1p first_order_rate_constant; k_dwee1p=0.2; real Cdc45(time) micromolar; when(time=time.min) Cdc45=0.01; real V_1cdc45 first_order_rate_constant; V_1cdc45=0.8; real Cdc45_tot micromolar; Cdc45_tot=0.5; real K_1cdc45 micromolar; K_1cdc45=0.02; real V_2cdc45 flux; V_2cdc45=0.12; real K_2cdc45 micromolar; K_2cdc45=0.02; real k_spol second_order_rate_constant; k_spol=0.8; real Pol_tot micromolar; Pol_tot=0.5; real Pol(time) micromolar; when(time=time.min) Pol=0.01; real k_dpol first_order_rate_constant; k_dpol=0.2; real Primer(time) micromolar; when(time=time.min) Primer=0.01; real k_sprim first_order_rate_constant; k_sprim=0.05; real k_dprim first_order_rate_constant; k_dprim=0.15; real k_aatr second_order_rate_constant; k_aatr=0.022; real ATR_tot micromolar; ATR_tot=0.5; real ATR(time) micromolar; when(time=time.min) ATR=0.01; real k_datr first_order_rate_constant; k_datr=0.15; real V_1chk first_order_rate_constant; V_1chk=4; real Chk1_tot micromolar; Chk1_tot=0.5; real K_1chk micromolar; K_1chk=0.5; real V_2chk flux; V_2chk=0.1; real K_2chk micromolar; K_2chk=0.5; real v_sw flux; v_sw=0; real BN(time) nanomolar; when(time=time.min) BN=0.1; // Var below replaced by constant in model eqns to satisfy unit correction // real n_gerard dimensionless; // n_gerard=4; real K_iw nanomolar; K_iw=0.5; real v_dw flux; v_dw=0.12; real K_dw micromolar; K_dw=0.5; real X(time) micromolar; when(time=time.min) X=0.01; real V_1x first_order_rate_constant; V_1x=10; real X_tot micromolar; X_tot=1; real K_1x micromolar; K_1x=0.1; real V_2x flux; V_2x=2; real K_2x micromolar; K_2x=0.1; real CbA(time) micromolar; when(time=time.min) CbA=0.01; real MP(time) nanomolar; when(time=time.min) MP=0.1; real vsP nano_flux; vsP=2.4; real vmP nano_flux; vmP=2.2; real kdmp first_order_rate_constant_nano; kdmp=0.02; real KAP nanomolar; KAP=0.6; real KmP nanomolar; KmP=0.3; // Var below replaced by constant in model eqns to satisfy unit correction // real n dimensionless; // n=2; real MC(time) nanomolar; when(time=time.min) MC=1.2; real vsC nano_flux; vsC=2.2; real vmC nano_flux; vmC=2; real kdmc first_order_rate_constant_nano; kdmc=0.02; real KAC nanomolar; KAC=0.6; real KmC nanomolar; KmC=0.4; real MB(time) nanomolar; when(time=time.min) MB=9; real vsB nano_flux; vsB=1.8; real vmB nano_flux; vmB=1.3; real kdmb first_order_rate_constant_nano; kdmb=0.02; real KIB nanomolar; KIB=2.2; real KmB nanomolar; KmB=0.4; // Var below replaced by constant in model eqns to satisfy unit correction // real m dimensionless; // m=2; real RN(time) nanomolar; when(time=time.min) RN=0.1; real MR(time) nanomolar; when(time=time.min) MR=1.5; real vsR nano_flux; vsR=1.6; real vmR nano_flux; vmR=1.6; real kdmr first_order_rate_constant_nano; kdmr=0.02; real KAR nanomolar; KAR=0.6; real KmR nanomolar; KmR=0.4; // Var below replaced by constant in model eqns to satisfy unit correction // real h dimensionless; // h=2; real PC(time) nanomolar; when(time=time.min) PC=0.1; real ksP first_order_rate_constant_nano; ksP=1.2; real Kp nanomolar; Kp=1.006; real Kdp nanomolar; Kdp=0.1; real k3 second_order_rate_constant_nano; k3=0.8; real k4 first_order_rate_constant_nano; k4=0.4; real kdn first_order_rate_constant_nano; kdn=0.02; real V1P nano_flux; V1P=9.6; real V2P nano_flux; V2P=0.6; real PCP(time) nanomolar; when(time=time.min) PCP=0.1; real PCC(time) nanomolar; when(time=time.min) PCC=0.1; real CC(time) nanomolar; when(time=time.min) CC=0.1; real ksC first_order_rate_constant_nano; ksC=3.2; real kdnc first_order_rate_constant_nano; kdnc=0.02; real V1C nano_flux; V1C=1.2; real V2C nano_flux; V2C=0.2; real CCP(time) nanomolar; when(time=time.min) CCP=0.1; real RC(time) nanomolar; when(time=time.min) RC=0.1; real ksR first_order_rate_constant_nano; ksR=1.7; real Kd nanomolar; Kd=0.3; real k9 first_order_rate_constant_nano; k9=0.8; real k10 first_order_rate_constant_nano; k10=0.4; real vdRC nano_flux; vdRC=4.4; real vdPC nano_flux; vdPC=3.4; real vdCC nano_flux; vdCC=1.4; real k1 first_order_rate_constant_nano; k1=0.8; real k2 first_order_rate_constant_nano; k2=0.4; real V1PC nano_flux; V1PC=2.4; real V2PC nano_flux; V2PC=0.2; real PCCP(time) nanomolar; when(time=time.min) PCCP=0.1; real PCN(time) nanomolar; when(time=time.min) PCN=0.1; real k7 second_order_rate_constant_nano; k7=1; real k8 first_order_rate_constant; k8=0.2; real V3PC nano_flux; V3PC=2.4; real V4PC nano_flux; V4PC=0.2; real PCNP(time) nanomolar; when(time=time.min) PCNP=0.1; real IN(time) nanomolar; when(time=time.min) IN=0.1; real vdRN nano_flux; vdRN=0.8; real vdPCC nano_flux; vdPCC=1.4; real vdPCN nano_flux; vdPCN=1.4; real BC(time) nanomolar; when(time=time.min) BC=0.1; real ksB first_order_rate_constant_nano; ksB=0.32; real k5 first_order_rate_constant_nano; k5=0.8; real k6 first_order_rate_constant_nano; k6=0.4; real V1B nano_flux; V1B=1.4; real V2B nano_flux; V2B=0.2; real BCP(time) nanomolar; when(time=time.min) BCP=0.1; real vdBC nano_flux; vdBC=3; real V3B nano_flux; V3B=1.4; real V4B nano_flux; V4B=0.4; real BNP(time) nanomolar; when(time=time.min) BNP=0.1; real vdBN nano_flux; vdBN=3; real vdIN nano_flux; vdIN=1.6; // // AP1:time=((v_sap1*GF/(K_agf+GF)-k_dap1*AP1)*eps); // pRB:time=((v_sprb-k_pc1*pRB*E2F+k_pc2*pRBc1-V_1*pRB/(K_1+pRB)*(Md+Mdp27)+V_2*pRBp/(K_2+pRBp)-k_dprb*pRB)*eps); // pRBc1:time=((k_pc1*pRB*E2F-k_pc2*pRBc1)*eps); // pRBp:time=((V_1*pRB/(K_1+pRB)*(Md+Mdp27)-V_2*pRBp/(K_2+pRBp)-V_3*pRBp/(K_3+pRBp)*Me+V_4*pRBpp/(K_4+pRBpp)-k_pc3*pRBp*E2F+k_pc4*pRBc2-k_dpRBp*pRBp)*eps); // pRBc2:time=((k_pc3*pRBp*E2F-k_pc4*pRBc2)*eps); // pRBpp:time=((V_3*pRBp/(K_3+pRBp)*Me-V_4*pRBpp/(K_4+pRBpp)-k_dpRBpp*pRBpp)*eps); // E2F:time=((v_se2f-k_pc1*pRB*E2F+k_pc2*pRBc1-k_pc3*pRBp*E2F+k_pc4*pRBc2-V_1e2f*Ma*E2F/(K_1e2f+E2F)+V_2e2f*E2Fp/(K_2e2f+E2Fp)-k_de2f*E2F)*eps); // E2Fp:time=((V_1e2f*Ma*E2F/(K_1e2f+E2F)-V_2e2f*E2Fp/(K_2e2f+E2Fp)-k_de2fp*E2Fp)*eps); // Cd:time=((k_cd1*AP1+k_cd2*E2F*K_i7/(K_i7+pRB)*K_i8/(K_i8+pRBp)-k_com1*Cd*(Cdk4_tot-(Mdi+Md+Mdp27))+k_decom1*Mdi-V_dd*Cd/(K_dd+Cd)-k_ddd*Cd)*eps); // Mdi:time=((k_com1*Cd*(Cdk4_tot-(Mdi+Md+Mdp27))-k_decom1*Mdi+V_m2d*Md/(K_2d+Md)-V_m1d*Mdi/(K_1d+Mdi))*eps); // Md:time=((V_m1d*Mdi/(K_1d+Mdi)-V_m2d*Md/(K_2d+Md)-k_c1*Md*p27+k_c2*Mdp27)*eps); // Mdp27:time=((k_c1*Md*p27-k_c2*Mdp27)*eps); // Ce:time=((k_ce*E2F*K_i9/(K_i9+pRB)*K_i10/(K_i10+pRBp)-k_com2*Ce*(Cdk2_tot-(Mei+Me+Mep27+Mai+Ma+Map27))+k_decom2*Mei-V_de*Skp2/(K_dceskp2+Skp2)*Ce/(K_de+Ce)-k_dde*Ce)*eps); // Mei:time=((k_com2*Ce*(Cdk2_tot-(Mei+Me+Mep27+Mai+Ma+Map27))-k_decom2*Mei+V_m2e*(Wee1+i_b1)*Me/(K_2e+Me)-V_m1e*Pe*Mei/(K_1e+Mei))*eps); // Me:time=((V_m1e*Pe*Mei/(K_1e+Mei)-V_m2e*(Wee1+i_b1)*Me/(K_2e+Me)-k_c3*Me*p27+k_c4*Mep27)*eps); // Skp2:time=((v_sskp2-V_dskp2*Skp2/(K_dskp2+Skp2)*Cdh1a/(K_cdh1+Cdh1a)-k_ddskp2*Skp2)*eps); // Mep27:time=((k_c3*Me*p27-k_c4*Mep27)*eps); // Pei:time=((v_spei+V_6e*(x_e1+x_e2*Chk1)*Pe/(K_6e+Pe)-V_m5e*(Me+a_e)*Pei/(K_5e+Pei)-k_dpei*Pei)*eps); // Pe:time=((V_m5e*(Me+a_e)*(Pei/(K_5e+Pei))-V_6e*(x_e1+x_e2*Chk1)*(Pe/(K_6e+Pe))-k_dpe*Pe)*eps); // Ca:time=((k_ca*E2F*K_i11/(K_i11+pRB)*K_i12/(K_i12+pRBp)-k_com3*Ca*(Cdk2_tot-(Mei+Me+Mep27+Mai+Ma+Map27))+k_decom3*Mai-V_da*Ca/(K_da+Ca)*Cdc20a/(K_acdc20+Cdc20a)-k_dda*Ca)*eps); // Mai:time=((k_com3*Ca*(Cdk2_tot-(Mei+Me+Mep27+Mai+Ma+Map27))-k_decom3*Mai+V_m2a*(Wee1+i_b2)*Ma/(K_2a+Ma)-V_m1a*Pa*Mai/(K_1a+Mai))*eps); // Ma:time=((V_m1a*Pa*Mai/(K_1a+Mai)-V_m2a*(Wee1+i_b2)*Ma/(K_2a+Ma)-k_c5*Ma*p27+k_c6*Map27)*eps); // Map27:time=((k_c5*Ma*p27-k_c6*Map27)*eps); // p27:time=((v_s1p27+v_s2p27*E2F*K_i13/(K_i13+pRB)*K_i14/(K_i14+pRBp)-k_c1*Md*p27+k_c2*Mdp27-k_c3*Me*p27+k_c4*Mep27-k_c5*Ma*p27+k_c6*Map27-k_c7*Mb*p27+k_c8*Mbp27-V_1p27*Me*p27/(K_1p27+p27)+V_2p27*p27p/(K_2p27+p27p)-k_ddp27*p27)*eps); // p27p:time=((V_1p27*Me*p27/(K_1p27+p27)-V_2p27*p27p/(K_2p27+p27p)-V_dp27p*Skp2/(K_dp27skp2+Skp2)*p27p/(K_dp27p+p27p)-k_ddp27p*p27p)*eps); // Cdh1i:time=((V_2cdh1*Cdh1a/(K_2cdh1+Cdh1a)*(Ma+Mb)-V_1cdh1*Cdh1i/(K_1cdh1+Cdh1i)-k_dcdh1i*Cdh1i)*eps); // Cdh1a:time=((v_scdh1a+V_1cdh1*Cdh1i/(K_1cdh1+Cdh1i)-V_2cdh1*Cdh1a/(K_2cdh1+Cdh1a)*(Ma+Mb)-k_dcdh1a*Cdh1a)*eps); // Pai:time=((v_spai+V_6a*(x_a1+x_a2*Chk1)*Pa/(K_6a+Pa)-V_m5a*(Ma+a_a)*Pai/(K_5a+Pai)-k_dpai*Pai)*eps); // Pa:time=((V_m5a*(Ma+a_a)*Pai/(K_5a+Pai)-V_6a*(x_a1+x_a2*Chk1)*Pa/(K_6a+Pa)-k_dpa*Pa)*eps); // Cb:time=((v_cb-k_com4*Cb*(Cdk1_tot-(Mbi+Mb+Mbp27))+k_decom4*Mbi-V_db*Cb/(K_db+Cb)*(Cdc20a/(K_dbcdc20+Cdc20a)+Cdh1a/(K_dbcdh1+Cdh1a))-k_ddb*Cb)*eps); // Mbi:time=((k_com4*Cb*(Cdk1_tot-(Mbi+Mb+Mbp27))-k_decom4*Mbi+V_m2b*(Wee1+i_b3)*Mb/(K_2b+Mb)-V_m1b*Pb*Mbi/(K_1b+Mbi))*eps); // Mb:time=((V_m1b*Pb*Mbi/(K_1b+Mbi)-V_m2b*(Wee1+i_b3)*Mb/(K_2b+Mb)-k_c7*Mb*p27+k_c8*Mbp27)*eps); // Mbp27:time=((k_c7*Mb*p27-k_c8*Mbp27)*eps); // Cdc20i:time=((v_scdc20i-V_m3b*Mb*Cdc20i/(K_3b+Cdc20i)+V_m4b*Cdc20a/(K_4b+Cdc20a)-k_dcdc20i*Cdc20i)*eps); // Cdc20a:time=((V_m3b*Mb*Cdc20i/(K_3b+Cdc20i)-V_m4b*Cdc20a/(K_4b+Cdc20a)-k_dcdc20a*Cdc20a)*eps); // Pbi:time=((v_spbi+V_6b*(x_b1+x_b2*Chk1)*Pb/(K_6b+Pb)-V_m5b*(Mb+a_b)*Pbi/(K_5b+Pbi)-k_dpbi*Pbi)*eps); // Pb:time=((V_m5b*(Mb+a_b)*Pbi/(K_5b+Pbi)-V_6b*(x_b1+x_b2*Chk1)*Pb/(K_6b+Pb)-k_dpb*Pb)*eps); // Wee1:time=((v_swee1+k_sw*Mw-V_m7b*(Mb+i_b)*Wee1/(K_7b+Wee1)+V_m8b*Wee1p/(K_8b+Wee1p)-k_dwee1*Wee1)*eps); // Wee1p:time=((V_m7b*(Mb+i_b)*Wee1/(K_7b+Wee1)-V_m8b*Wee1p/(K_8b+Wee1p)-k_dwee1p*Wee1p)*eps); // Cdc45:time=((V_1cdc45*Me*(Cdc45_tot-Cdc45)/(K_1cdc45+(Cdc45_tot-Cdc45))-V_2cdc45*Cdc45/(K_2cdc45+Cdc45)-k_spol*(Pol_tot-Pol)*Cdc45+k_dpol*Pol)*eps); // Pol:time=((k_spol*(Pol_tot-Pol)*Cdc45-k_dpol*Pol)*eps); // Primer:time=((k_sprim*Pol-k_dprim*Primer-k_aatr*(ATR_tot-ATR)*Primer+k_datr*ATR)*eps); // ATR:time=((k_aatr*(ATR_tot-ATR)*Primer-k_datr*ATR)*eps); // Chk1:time=((V_1chk*ATR*(Chk1_tot-Chk1)/(K_1chk+(Chk1_tot-Chk1))-V_2chk*Chk1/(K_2chk+Chk1))*eps); // Mw:time=(v_sw*BN^4/(K_iw^4+BN^4)-v_dw*Mw/(K_dw+Mw)); // X:time=((V_1x*Ma*((X_tot-X)/(K_1x+(X_tot-X)))-V_2x*(X/(K_2x+X)))*eps); // CbA:time=((v_cb*X*(1 per_micromolar)-k_com4*CbA*(Cdk1_tot-(Mbi+Mb+Mbp27))+k_decom4*Mbi-V_db*(CbA/(K_db+CbA))*(Cdc20a/(K_dbcdc20+Cdc20a)+Cdh1a/(K_dbcdh1+Cdh1a))-k_ddb*CbA)*eps); // MP:time=(vsP*BN^2/(KAP^2+BN^2)-(vmP*MP/(KmP+MP)+kdmp*MP)); // MC:time=(vsC*BN^2/(KAC^2+BN^2)-(vmC*MC/(KmC+MC)+kdmc*MC)); // MB:time=(vsB*KIB^2/(KIB^2+RN^2)-(vmB*MB/(KmB+MB)+kdmb*MB)); // MR:time=(vsR*BN^2/(KAR^2+BN^2)-(vmR*MR/(KmR+MR)+kdmr*MR)); // PC:time=(ksP*MP+V2P*PCP/(Kdp+PCP)+k4*PCC-(V1P*PC/(Kp+PC)+k3*PC*CC+kdn*PC)); // CC:time=(ksC*MC+V2C*CCP/(Kdp+CCP)+k4*PCC-(V1C*CC/(Kp+CC)+k3*PC*CC+kdnc*CC)); // RC:time=(ksR*MR+k10*RN-(k9*RC+vdRC*RC/(Kd+RC)+kdn*RC)); // PCP:time=(V1P*PC/(Kp+PC)-(V2P*PCP/(Kdp+PCP)+vdPC*PCP/(Kd+PCP)+kdn*PCP)); // CCP:time=(V1C*CC/(Kp+CC)-(V2C*CCP/(Kdp+CCP)+vdCC*CCP/(Kd+CCP)+kdn*CCP)); // PCC:time=(V2PC*PCCP/(Kdp+PCCP)+k3*PC*CC+k2*PCN-(V1PC*PCC/(Kp+PCC)+k4*PCC+k1*PCC+kdn*PCC)); // PCN:time=(V4PC*PCNP/(Kdp+PCNP)+k1*PCC+k8*IN-(V3PC*PCN/(Kp+PCN)+k2*PCN+k7*BN*PCN+kdn*PCN)); // RN:time=(k9*RC-(k10*RN+vdRN*RN/(Kd+RN)+kdn*RN)); // PCCP:time=(V1PC*PCC/(Kp+PCC)-(V2PC*PCCP/(Kdp+PCCP)+vdPCC*PCCP/(Kd+PCCP)+kdn*PCCP)); // PCNP:time=(V3PC*PCN/(Kp+PCN)-(V4PC*PCNP/(Kdp+PCNP)+vdPCN*PCNP/(Kd+PCNP)+kdn*PCNP)); // BC:time=(V2B*BCP/(Kdp+BCP)+k6*BN+ksB*MB-(V1B*BC/(Kp+BC)+k5*BC+kdn*BC)); // BCP:time=(V1B*BC/(Kp+BC)-(V2B*BCP/(Kdp+BCP)+vdBC*BCP/(Kd+BCP)+kdn*BCP)); // BN:time=(V4B*BNP/(Kdp+BNP)+k5*BC+k8*IN-(V3B*BN/(Kp+BN)+k6*BN+k7*BN*PCN+kdn*BN)); // BNP:time=(V3B*BN/(Kp+BN)-(V4B*BNP/(Kdp+BNP)+vdBN*BNP/(Kd+BNP)+kdn*BNP)); // IN:time=(k7*BN*PCN-(k8*IN+vdIN*IN/(Kd+IN)+kdn*IN)); // }