Fig 4. Evaluation of model plausibilities from the α2β2γ3 KD MPSA against data-informed constraints.
A) Workflow of the progressive elimination of implausible models. After partitioning out the simulations into ADP-dominant (left boxes, >80% ADP-frac) or ADP non-dominant cases (right boxes, <80% ADP-frac), we then imposed data-informed constraints on the parameter values and ratios. The labels located in between the workflow boxes represent criteria for identifying models as implausible. B-E) The panels from left to right show the progressive elimination of implausible models from the simulations in the α2β2γ3 KD MPSA in which ADP-p-AMPK contributed less than 0.8 of the time integral of AMPK activity. The panels from left to right correspond to the models featured in the blue-shaded boxes from top to bottom in panel A. Points and curves colored green or blue indicate simulations with fractions of ADP control that tend to either ADP- or AMP-dominant control, respectively. The upper panels display the log10 values of the quantities shown in the top label of each plot for the labelled AMPK complexes below each plot. The green and blue points indicate values from models exhibiting ADP- and AMP-dominant control, respectively. The grey lines indicate implausible relative parameter values between ATP-p-AMPK and ADP-p-AMPK, whereas the black-hatched lines indicate implausible relative parameter values between ATP-p-AMPK and AMP-p-AMPK. which were subsequently eliminated. The lower panels represent the corresponding time courses of p-AMPK. The “Median Integral Ratio” and “Minimum Integral Ratio” correspond to the median and minimum values for the fractions of ADP control for the ensemble of models. B) First pass, simulations in which the Vmax/KM values of the kinase for ADP-AMPK and AMP-AMPK were lower than ATP-AMPK. C) Second pass, simulations in which the Vmax values of the kinase for ADP-AMPK and AMP-AMPK were lower than those for ATP-AMPK. D) Third pass, simulations in which the Vmax/KM of the phosphatase for ADP-p-AMPK and AMP-p-AMPK were higher than ATP-p-AMPK. E) Fourth pass, removing simulations in which the Vmax of the phosphatase for ADP-p-AMPK and AMP-p-AMPK were higher than ATP-p-AMPK.