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Chaos and birhythmicity in a model for circadian oscillations of the PER and TIM proteins in drosophila

  • Jean-Christophe Leloup
  • Albert Goldbeter
J. Theor. Biol. 1999; 198 (3): 445-459
Abstract
In Drosophila, circadian oscillations in the levels of two proteins, PER and TIM, result from the negative feedback exerted by a PER-TIM complex on the expression of the per and tim genes which code for these two proteins. On the basis of these experimental observations, we have recently proposed a theoretical model for circadian oscillations of the PER and TIM proteins in Drosophila. Here we show that for constant environmental conditions this model is capable of generating autonomous chaotic oscillations. For other parameter values, the model can also display birhythmicity, i.e. the coexistence between two stable regimes of limit cycle oscillations. We analyse the occurrence of chaos and birhythmicity by means of bifurcation diagrams and locate the different domains of complex oscillatory behavior in parameter space. The relative smallness of these domains raises doubts as to the possible physiological significance of chaos and birhythmicity in regard to circadian rhythm generation. Beyond the particular context of circadian rhythms we discuss the results in the light of other mechanisms underlying chaos and birhythmicity in regulated biological systems. Copyright 1999 Academic Press.

Unit definitions have no effect on the numerical analysis of the model. It remains the responsibility of the modeler to ensure the internal numerical consistency of the model. If units are provided, however, the consistency of the model units will be checked.

Name Definition
1e-09 mole
3600.0 second
Id Name Spatial dimensions Size
Cell cytoplasm 3.0 1.0
compartment_0000002 nucleus 3.0 1.0
Id Name Initial quantity Compartment Fixed
CC Cytosolic PER-TIM Complex 0.0 Cell (cytoplasm)
Cn Nuclear PER-TIM Complex 0.0 compartment_0000002 (nucleus)
Mp PER mRNA 0.0 Cell (cytoplasm)
Mt TIM mRNA 0.0 Cell (cytoplasm)
P0 PER Protein (unphosphorylated) 0.0 Cell (cytoplasm)
P1 PER Protein (mono-phosphorylated) 0.0 Cell (cytoplasm)
P2 PER Protein (bi-phosphorylated) 0.0 Cell (cytoplasm)
T0 TIM Protein (unphosphorylated) 0.0 Cell (cytoplasm)
T1 TIM Protein (mono-phosphorylated) 0.0 Cell (cytoplasm)
T2 TIM Protein (bi-phosphorylated) 0.0 Cell (cytoplasm)

Initial assignments are expressions that are evaluated at time=0. It is not recommended to create initial assignments for all model entities. Restrict the use of initial assignments to cases where a value is expressed in terms of values or sizes of other model entities. Note that it is not permitted to have both an initial assignment and an assignment rule for a single model entity.

Definition
Id Name Objective coefficient Reaction Equation and Kinetic Law Flux bounds
Mp_degradation PER mRNA degradation Mp > ∅

Cell * k_d * Mp + Cell * V_mP * Mp / (K_mP + Mp)
Mp_production PER mRNA production ∅ > Mp

Cell * v_sP * pow(K_IP, n) / (pow(K_IP, n) + pow(Cn, n))
Mt_degradation TIM mRNA degradation Mt > ∅

Cell * k_d * Mt + Cell * V_mT * Mt / (K_mT + Mt)
Mt_production TIM mRNA production ∅ > Mt

Cell * V_sT * pow(K_IT, n) / (pow(K_IT, n) + pow(Cn, n))
P0_degradation PER degradation P0 > ∅

Cell * k_d * P0
P0_production PER production ∅ > P0

Cell * k_sP * Mp
P0_to_P1 First Phosphorylation of PER P0 > P1

Cell * V_1P * P0 / (K1_P + P0)
P1_degradation PER-1 degradation P1 > ∅

Cell * k_d * P1
P1_to_P0 Dephosphorylation of PER (1st P) P1 > P0

Cell * V_2P * P1 / (K_2P + P1)
P1_to_P2 Second Phosphorylation of PER P1 > P2

Cell * V_3P * P1 / (K_3P + P1)
P2_degradation PER-2 degradation P2 > ∅

Cell * k_d * P2 + Cell * V_dP * P2 / (K_dP + P2)
P2_to_P1 Dephosphorylation of PER (2nd P) P2 > P1

Cell * V_4P * P2 / (K_4P + P2)
PT_complex_degradation PER-TIM complex degradation (cytosol) CC > ∅

Cell * k_dC * CC
PT_complex_formation PER-TIM complex formation P2 + T2 = CC

Cell * k3 * P2 * T2 - Cell * k4 * CC
PT_complex_nucleation PER-TIM complex nucleation CC = Cn

Cell * k1 * CC - compartment_0000002 * k2 * Cn
PTnucl_complex_degradation PER-TIM complex degradation (nuclear) Cn > ∅

compartment_0000002 * k_dN * Cn
T0_degradation TIM degradation T0 > ∅

Cell * k_d * T0
T0_production TIM production ∅ > T0

Cell * k_sT * Mt
T0_to_T1 First Phosphorylation of TIM T0 > T1

Cell * V_1T * T0 / (K_1T + T0)
T1_degradation TIM-1 degradation T1 > ∅

Cell * k_d * T1
T1_to_T0 Dephosphorylation of TIM (1st P) T1 > T0

Cell * V_2T * T1 / (K_2T + T1)
T1_to_T2 Second Phosphorylation of TIM T1 > T2

Cell * V_3T * T1 / (K_3T + T1)
T2_degradation TIM-2 degradation T2 > ∅

Cell * k_d * T2 + Cell * V_dT * T2 / (K_dT + T2)
T2_to_T1 Dephosphorylation of TIM (2nd P) T2 > T1

Cell * V_4T * T2 / (K_4T + T2)

Global parameters

Id Value
Pt 0.0
Tt 0.0
V_dT 2.0
V_mT 0.7

Local parameters

Id Value Reaction
k_d 0.01 Mp_degradation (PER mRNA degradation)
V_mP 0.7 Mp_degradation (PER mRNA degradation)
K_mP 0.2 Mp_degradation (PER mRNA degradation)
v_sP 1.0 Mp_production (PER mRNA production)
K_IP 1.0 Mp_production (PER mRNA production)
n 4.0 Mp_production (PER mRNA production)
k_d 0.01 Mt_degradation (TIM mRNA degradation)
K_mT 0.2 Mt_degradation (TIM mRNA degradation)
V_sT 1.0 Mt_production (TIM mRNA production)
K_IT 1.0 Mt_production (TIM mRNA production)
n 4.0 Mt_production (TIM mRNA production)
k_d 0.01 P0_degradation (PER degradation)
k_sP 0.9 P0_production (PER production)
K1_P 2.0 P0_to_P1 (First Phosphorylation of PER)
V_1P 8.0 P0_to_P1 (First Phosphorylation of PER)
k_d 0.01 P1_degradation (PER-1 degradation)
K_2P 2.0 P1_to_P0 (Dephosphorylation of PER (1st P))
V_2P 1.0 P1_to_P0 (Dephosphorylation of PER (1st P))
K_3P 2.0 P1_to_P2 (Second Phosphorylation of PER)
V_3P 8.0 P1_to_P2 (Second Phosphorylation of PER)
k_d 0.01 P2_degradation (PER-2 degradation)
V_dP 2.0 P2_degradation (PER-2 degradation)
K_dP 0.2 P2_degradation (PER-2 degradation)
K_4P 2.0 P2_to_P1 (Dephosphorylation of PER (2nd P))
V_4P 1.0 P2_to_P1 (Dephosphorylation of PER (2nd P))
k_dC 0.01 PT_complex_degradation (PER-TIM complex degradation (cytosol))
k3 1.2 PT_complex_formation (PER-TIM complex formation)
k4 0.6 PT_complex_formation (PER-TIM complex formation)
k1 0.6 PT_complex_nucleation (PER-TIM complex nucleation)
k2 0.2 PT_complex_nucleation (PER-TIM complex nucleation)
k_dN 0.01 PTnucl_complex_degradation (PER-TIM complex degradation (nuclear))
k_d 0.01 T0_degradation (TIM degradation)
k_sT 0.9 T0_production (TIM production)
K_1T 2.0 T0_to_T1 (First Phosphorylation of TIM)
V_1T 8.0 T0_to_T1 (First Phosphorylation of TIM)
k_d 0.01 T1_degradation (TIM-1 degradation)
K_2T 2.0 T1_to_T0 (Dephosphorylation of TIM (1st P))
V_2T 1.0 T1_to_T0 (Dephosphorylation of TIM (1st P))
K_3T 2.0 T1_to_T2 (Second Phosphorylation of TIM)
V_3T 8.0 T1_to_T2 (Second Phosphorylation of TIM)
k_d 0.01 T2_degradation (TIM-2 degradation)
K_dT 0.2 T2_degradation (TIM-2 degradation)
K_4T 2.0 T2_to_T1 (Dephosphorylation of TIM (2nd P))
V_4T 1.0 T2_to_T1 (Dephosphorylation of TIM (2nd P))

Assignment rules

Definition
Tt = CC + Cn + T0 + T1 + T2
Pt = CC + Cn + P0 + P1 + P2

Rate rules

Definition

Algebraic rules

Definition
Definition
Trigger Assignments