(* Generated by JWS Online *) (* This is an experimental feature of JWS Online. Please report any mistakes.*) (* Note that the following notable SBML entities or features are not supported in notebook outputyet: *) (* Events *) (* Constraints *) (* Units and UnitDefinitions *) (* AlgebraicRules *) (* conversionFactors *) variables = { AkttBaF3[t], BaF3Epo[t], EpoRBaF3[t], ErktBaF3[t], GTPRas[t], IntpS6[t], Intpakt[t], Intperk[t], MektBaF3[t], PDK1tBaF3[t], PI3KtBaF3[t], PI45P2BaF3[t], PIP3[t], PIP3Akt[t], PIP3PDK1[t], PTENBaF3[t], PhosphatasetBaF3[t], Proliferation[t], RSKa[t], RSKtb[t], RaftBaF3[t], Raptorb[t], RastBaF3[t], Rictorb[t], RpSHIP1[t], RpSos[t], S6tBaF3[t], SHIP1tBaF3[t], TORC1[t], TORC2[t], actPhosphatase[t], mTORa[t], mTORt[t], pAkt[t], pEpoR[t], pErk[t], pMek[t], pRaf[t], pS6[t], pSos[t], phos2[t], ppErk[t], ppMek[t] }; initialValues = { AkttBaF3[0] == 0.51, BaF3Epo[0] == 0.002, EpoRBaF3[0] == 0.01862, ErktBaF3[0] == 2.964, GTPRas[0] == 0.17879248230044018, IntpS6[0] == 0.0, Intpakt[0] == 0.0, Intperk[0] == 0.0, MektBaF3[0] == 4.38, PDK1tBaF3[0] == 0.763, PI3KtBaF3[0] == 0.0124, PI45P2BaF3[0] == 10, PIP3[0] == 0.0014259096174786036, PIP3Akt[0] == 0.296484152509495, PIP3PDK1[0] == 0.004335113669239996, PTENBaF3[0] == 0.1074, PhosphatasetBaF3[0] == 0.0415, Proliferation[0] == 0.0, RSKa[0] == 0.06843365642650674, RSKtb[0] == 3.0306, RaftBaF3[0] == 3.886, Raptorb[0] == 0.1, RastBaF3[0] == 9.531, Rictorb[0] == 1.2329, RpSHIP1[0] == 0, RpSos[0] == 0.0, S6tBaF3[0] == 2.59, SHIP1tBaF3[0] == 0.0842, TORC1[0] == 0, TORC2[0] == 0.0, actPhosphatase[0] == 0.0, mTORa[0] == 0.0, mTORt[0] == 0.1, pAkt[0] == 0.0025557633868391167, pEpoR[0] == 0.0, pErk[0] == 0.017777899006355905, pMek[0] == 4.312731699382008, pRaf[0] == 0.00032128827441495054, pS6[0] == 0.0003669720694067856, pSos[0] == 0.0, phos2[0] == 0.0, ppErk[0] == 0.005858735624008178, ppMek[0] == 0.010369614478384468 }; rates = { v1, v18, v19, v2, v20, v21, v22, v23, v24, v25, v26, v27, v28, v29, v3, v30, v31, v32, v33, v34, v35, v36, v37, v38, v39, v4, v40, v41, v42, v43, v44, v45, v46, v47, v48, v49, v5, v50, v51, v52, v53, v54, v55, v56, v57, v58, v59, v6, v60, v61, v62, v63, v64, v65, v66, v67, v68, v69, v7, v71, v73 }; rateEquations = { v1 -> Epodegradation*BaF3Epo[t], v18 -> kSHIP1*(pEpoR[t] - RpSHIP1[t])*(-RpSHIP1[t] + SHIP1tBaF3[t]), v19 -> lSHIP1*RpSHIP1[t], v2 -> (EpoRactivation1*BaF3Epo[t]^nb*(EpoRBaF3[t] - (1 + kPI3K/(1 + kPI3K + kPI3K*kPI3Kras) + (kPI3K*kPI3Kras)/(1 + kPI3K + kPI3K*kPI3Kras))*pEpoR[t]))/((ksatb^nb + BaF3Epo[t]^nb)*(1 + phos2[t]/Ki1)), v20 -> (kPI3K*vPIP3*pEpoR[t]*PI45P2BaF3[t])/(1 + kPI3K + kPI3K*kPI3Kras), v21 -> (kPI3K*kPI3Kras*main1*vPIP3*pEpoR[t]*PI45P2BaF3[t])/(1 + kPI3K + kPI3K*kPI3Kras), v22 -> kshbasal*PIP3[t]*(-RpSHIP1[t] + SHIP1tBaF3[t]), v23 -> vPI45P2*PIP3[t]*PTENBaF3[t], v24 -> vPI34P2*PIP3[t]*RpSHIP1[t], v25 -> kPDK1*PIP3[t]*(PDK1tBaF3[t] - PIP3PDK1[t]), v26 -> lPDK1*PIP3PDK1[t], v27 -> kAkt*PIP3[t]*(AkttBaF3[t] - pAkt[t] - PIP3Akt[t]), v28 -> lAkt*PIP3Akt[t], v29 -> vpAkt*PIP3Akt[t]*PIP3PDK1[t], v3 -> Phosphataseactivation1*pEpoR[t]*(-actPhosphatase[t] + PhosphatasetBaF3[t]), v30 -> vpAkt*PIP3Akt[t]*PIP3PDK1[t], v31 -> (vpAkt*PIP3Akt[t]*PIP3PDK1[t])/(1 + Aktin*kaktinb), v32 -> dpAkt*pAkt[t], v33 -> vPIP3basal*(-((kPI3K*pEpoR[t])/(1 + kPI3K + kPI3K*kPI3Kras)) - (kPI3K*kPI3Kras*pEpoR[t])/(1 + kPI3K + kPI3K*kPI3Kras) + PI3KtBaF3[t])*PI45P2BaF3[t], v34 -> main1*vPIP3basal*PI45P2BaF3[t], v35 -> kpes*ppErk[t]*(Sostb - pSos[t] - RpSos[t]), v36 -> kdpes*pSos[t], v37 -> kSos*(pEpoR[t] - RpSos[t])*(Sostb - pSos[t] - RpSos[t]), v38 -> lSos*RpSos[t], v39 -> kpes*ppErk[t]*RpSos[t], v4 -> Phosphatasedeactivation1*actPhosphatase[t], v40 -> kbackRas*(-GTPRas[t] - (kPI3K*kPI3Kras*pEpoR[t])/(1 + kPI3K + kPI3K*kPI3Kras) + RastBaF3[t]), v41 -> kaRas*(-GTPRas[t] - (kPI3K*kPI3Kras*pEpoR[t])/(1 + kPI3K + kPI3K*kPI3Kras) + RastBaF3[t])*RpSos[t], v42 -> kdRas*GTPRas[t], v43 -> kpRaf*(GTPRas[t] + (kPI3K*kPI3Kras*pEpoR[t])/(1 + kPI3K + kPI3K*kPI3Kras))*(-pRaf[t] + RaftBaF3[t]), v44 -> lpRaf*pRaf[t], v45 -> kpMek*(MektBaF3[t] - pMek[t] - ppMek[t])*pRaf[t], v46 -> lpMek*pMek[t], v47 -> kppMek*pMek[t]*pRaf[t], v48 -> lppMek*ppMek[t], v49 -> kpErk*(ErktBaF3[t] - pErk[t] - ppErk[t])*ppMek[t], v5 -> pEpoRdeactivation1*actPhosphatase[t]*pEpoR[t], v50 -> bDUSP3*lpErk*pErk[t], v51 -> (kppErk*pErk[t]*ppMek[t])/(1 + kmekinb*Mekin), v52 -> bDUSP3*lppErk*ppErk[t], v53 -> ppErk[t], v54 -> pAkt[t], v55 -> kvpakt*pAkt[t]*(-mTORa[t] + mTORt[t] - TORC1[t] - TORC2[t]), v56 -> (kvppErk*RSKa[t]*(-mTORa[t] + mTORt[t] - TORC1[t] - TORC2[t]))/(1 + kinrskb*RSKin), v57 -> kdactm*mTORa[t], v58 -> (kst1*(Raptorb[t] - TORC1[t])*(mTORa[t] - TORC1[t] - TORC2[t]))/(1 + kinrapab*Rapamycin), v59 -> kdt1*TORC1[t], v6 -> (Phosact1*pEpoR[t]^n1)/(Ji1^n1 + pEpoR[t]^n1), v60 -> kdactm*TORC1[t], v61 -> kst2*(Rictorb[t] - TORC2[t])*(mTORa[t] - TORC1[t] - TORC2[t]), v62 -> kdt2*TORC2[t], v63 -> kdactm*TORC2[t], v64 -> (karsk*ppErk[t]*(-RSKa[t] + RSKtb[t]))/(1 + kinrskb*RSKin), v65 -> kdrsk*RSKa[t], v66 -> kas6t*(-pS6[t] + S6tBaF3[t])*TORC1[t], v67 -> kas6r*RSKa[t]*(-pS6[t] + S6tBaF3[t]), v68 -> kbacks6*(-pS6[t] + S6tBaF3[t]), v69 -> kdphoss6*pS6[t], v7 -> Phosdeact1*phos2[t], v71 -> pS6[t], v73 -> pboffcorrect/60 + (pbk2correct*(cycleaktinb*pAkt[t] + cyclemekinb*ppErk[t]))/maxccb }; parameters = { Aktin -> 0.0, EpoRactivation1 -> 0.140964, Epodegradation -> 0.0173287, Ji1 -> 0.220505, Ki1 -> 0.0272784, Mekin -> 0.0, Phosact1 -> 341.317, Phosdeact1 -> 1*^-05, Phosphataseactivation1 -> 144.425, Phosphatasedeactivation1 -> 1*^-05, RSKin -> 0.0, Rapamycin -> 0.0, Sostb -> 4.46181*^-05, bDUSP3 -> 96.7699, cycleaktinb -> 0.967522, cyclemekinb -> 0.127989, dpAkt -> 3.4739, initAkttBaF3 -> 0.51, initErktBaF3 -> 2.964, initMektBaF3 -> 4.38, initPDK1tBaF3 -> 0.763, initPI3KtBaF3 -> 0.0124, initPI45P2BaF3 -> 10.0, initPTENBaF3 -> 0.1074, initRSKtb -> 3.0306, initRaftBaF3 -> 3.886, initRastBaF3 -> 9.531, initRpSHIP1 -> 0.0, initS6tBaF3 -> 2.59, initSHIP1tBaF3 -> 0.0842, initTORC1 -> 0.0, kAkt -> 9984.96, kPDK1 -> 9439.5, kPI3K -> 0.000104741, kPI3Kras -> 10000.0, kSHIP1 -> 0.0745937, kSos -> 59.4049, kaRas -> 2981.53, kaktinb -> 1.866219406, karsk -> 1.26435, kas6r -> 0.000533083, kas6t -> 2180.44, kbackRas -> 0.0103384, kbacks6 -> 1.00003*^-05, kdRas -> 0.540777, kdactm -> 0.0617342, kdpes -> 0.0270729, kdphoss6 -> 0.328006, kdrsk -> 0.677229, kdt1 -> 1588.13, kdt2 -> 1*^-05, kinrapab -> 2.778901656, kinrskb -> 0.552054462, kmekinb -> 3.224998336, kpErk -> 9999.08, kpMek -> 9774.26, kpRaf -> 1.17959, kpes -> 0.583255, kppErk -> 9999.96, kppMek -> 9999.77, ksatb -> 0.0024577, kshbasal -> 1*^-05, kst1 -> 20.0908, kst2 -> 0.0619403, kvpakt -> 0.000174996, kvppErk -> 0.000282332, lAkt -> 10.1007, lPDK1 -> 2355.54, lSHIP1 -> 0.000650697, lSos -> 0.39616, lpErk -> 177.216, lpMek -> 0.0414313, lpRaf -> 2549.69, lppErk -> 3.2516, lppMek -> 1336.21, main1 -> 0.000224787, maxccb -> 0.99, n1 -> 4.0, nb -> 2.03939, pEpoRdeactivation1 -> 3.20488, pbk2correct -> 0.485791, pboffcorrect -> 0.470245, vPI34P2 -> 9996.96, vPI45P2 -> 84.5564, vPIP3 -> 10000.0, vPIP3basal -> 0.104429, vpAkt -> 6.90774, cyt -> 1.0 }; assignments = { pS6plot -> 412.8573*pS6[t] }; events = { }; speciesAnnotations = { }; reactionAnnotations = { }; units = { {"time" -> "", "metabolite" -> "", "extent" -> ""} }; (* Time evolution *) odes = { AkttBaF3'[t] == 0.0 , BaF3Epo'[t] == -1.0*v1, EpoRBaF3'[t] == 0.0 , ErktBaF3'[t] == 0.0 , GTPRas'[t] == 1.0*v40 +1.0*v41 -1.0*v42, IntpS6'[t] == 1.0*v71 , Intpakt'[t] == 1.0*v54 , Intperk'[t] == 1.0*v53 , MektBaF3'[t] == 0.0 , PDK1tBaF3'[t] == 0.0 , PI3KtBaF3'[t] == 0.0 , PI45P2BaF3'[t] == 0.0 , PIP3'[t] == 1.0*v20 +1.0*v21 +1.0*v26 +1.0*v28 +1.0*v30 +1.0*v33 +1.0*v34 -1.0*v22 -1.0*v23 -1.0*v24 -1.0*v25 -1.0*v27, PIP3Akt'[t] == 1.0*v27 -1.0*v28 -1.0*v29, PIP3PDK1'[t] == 1.0*v25 -1.0*v26, PTENBaF3'[t] == 0.0 , PhosphatasetBaF3'[t] == 0.0 , Proliferation'[t] == 1.0*v73 , RSKa'[t] == 1.0*v64 -1.0*v65, RSKtb'[t] == 0.0 , RaftBaF3'[t] == 0.0 , Raptorb'[t] == 0.0 , RastBaF3'[t] == 0.0 , Rictorb'[t] == 0.0 , RpSHIP1'[t] == 1.0*v18 -1.0*v19, RpSos'[t] == 1.0*v37 -1.0*v38 -1.0*v39, S6tBaF3'[t] == 0.0 , SHIP1tBaF3'[t] == 0.0 , TORC1'[t] == 1.0*v58 -1.0*v59 -1.0*v60, TORC2'[t] == 1.0*v61 -1.0*v62 -1.0*v63, actPhosphatase'[t] == 1.0*v3 -1.0*v4, mTORa'[t] == 1.0*v55 +1.0*v56 +1.0*v59 +1.0*v62 -1.0*v57 -1.0*v58 -1.0*v61, mTORt'[t] == 0.0 , pAkt'[t] == 1.0*v31 -1.0*v32, pEpoR'[t] == 1.0*v2 -1.0*v5, pErk'[t] == 1.0*v49 +1.0*v52 -1.0*v50 -1.0*v51, pMek'[t] == 1.0*v45 +1.0*v48 -1.0*v46 -1.0*v47, pRaf'[t] == 1.0*v43 -1.0*v44, pS6'[t] == 1.0*v66 +1.0*v67 +1.0*v68 -1.0*v69, pSos'[t] == 1.0*v35 +1.0*v39 -1.0*v36, phos2'[t] == 1.0*v6 -1.0*v7, ppErk'[t] == 1.0*v51 -1.0*v52, ppMek'[t] == 1.0*v47 -1.0*v48 }; timeCourse = NDSolve[Join[odes, initialValues]//.rateEquations//.assignments//.parameters, variables, {t, 0, 100}]; (* Steady-state solution initialized with result of time evolution *) findRootEquations = odes /.D[_[t],t]->0; findRootVariables = Partition[Flatten[{#, #/.timeCourse/.t->100} &/@variables],2]; steadyStateVariables = FindRoot[findRootEquations//.rateEquations//.assignments//.parameters, findRootVariables, MaxIterations->100] fluxes = #//.assignments//.parameters/.steadyStateVariables&/@rateEquations (* Plot the time evolution of the variables *) plotTable=Table[Plot[variables[[i]]/.parameters/.timeCourse,{t,0,100},PlotLegends->variables[[i]],PlotRange->Full],{i,Length[variables]}]