Basal State Calibration of a Chemical Reaction Network Model for Autophagy.

Abstract

The modulation of autophagy plays a dual role in tumor cells, with the potential to both promote and suppress tumor proliferation. In order to gain a deeper understanding of the nature of autophagy, we have developed a chemical reaction kinetic model of autophagy and apoptosis based on the mass action kinetic models that have been previously described in the literature. It is regrettable that the authors did not provide all of the information necessary to reconstruct their model, which made their simulation results irreproducible. In this study, based on an extensive literature review, we have identified concentrations for each species in the stress-free, homeostatic state. These ranges were randomly sampled to generate sets of initial concentrations, from which the simulations were run. In every case, abnormal behavior was observed, with apoptosis and autophagy being activated, even in the absence of stress. Consequently, the model failed to reproduce even the basal conditions. Detailed examination of the model revealed erroneous reactions, which were corrected. The influential kinetic parameters of the corrected model were identified and optimized using the Optima++ code. The model is now capable of simulating homeostatic states, and provides a suitable basis for further model development to describe cell response to various stresses.