Sensitivity of AP-1 to perturbations in network parameters
: Simulated response of Total AP-1 DNA binding activity as well as its constituent
dimers to Ang II stimulus. Note that these profiles are repeated from Figure 3 to
facilitate direct interpretation of the AP-1 activity time series in the context of
sensitivity analysis. The composition of Total AP-1 activity has been highlighted
by the rectangles at three time points of interest.
: Dynamic profiles of total-effects sensitivity indices of Total AP-1 for the top
seven most sensitive model parameters (1: ppc-Fos:ppc-Jun dephosphorylation, 2: FRK
dynamics, 3: c-Jun pre-mRNA synthesis, 4: ppc-Jun:ppc-Jun dephosphorylation, 5: c-Jun
translation, 6: pc-Jun phosphorylation, 7: JNK dynamics). (B-D)
Contribution of first-order effects (white inset) to the AP-1 activity total effects
sensitivities calculated at (B) 20, (C) 40, and (D) 60 minutes after Ang II treatment.
Gray and black bars correspond to Fos:Jun and Jun:Jun arms of the network, respectively.
Parameter index matches the ordering in (A). Bar coloring corresponds to mechanisms
relating to activation of ppc-Fos:ppc-Jun (light grey) or ppc-Jun:ppc-Jun (black)
as shown in Figure 2. (E-G)
DyNSIM representation of global sensitivity analysis results in network context at
(E) 20, (F) 40, and (G) 60 minutes after Ang II treatment. Total AP-1 activity is
indicated in the purple rectangle, while line thickness indicates sensitivity of Total
AP-1 activity to the reaction mechanisms index of (A). A detailed description of network
nodes is presented in Figure 2. Sensitivity analysis of Total AP-1 was performed during
15-60 minutes of Ang II treatment when the variance of simulated Total AP-1 activity
levels was greater than 1% of the maximum variance to avoid numerical oddities affecting
the sensitivity calculations.