Validation of a model of the GAL regulatory system via robustness analysis of its bistability characteristics

Background: In Saccharomyces cerevisiae, structural bistability generates a bimodal expression of the galactose uptake genes (GAL) when exposed to low and high glucose concentrations. This indicates that yeast cells can decide between using either the limited amount of glucose or growing on galactose under changing environmental conditions. A crucial requirement for any plausible mechanistic model of this system is that it reproduces the robustness of the bistable response observed in vivo against inter-individual parametric variability and fluctuating environmental conditions. Results: We show how a control-theoretic analysis of the robustness of a model of the GAL regulatory network may be used to establish the model's plausibility in characterizing the persistent memory of different carbon sources, without the need for extensive simulations. Chemical Reaction Network Theory is used to establish that the proposed network model is compatible with structural bistability. The robustness of each of the two operative conditions against fluctuations of the species concentrations is demonstrated by studying the Domains of Attraction of the corresponding equilibrium points. Finally, we use a global robustness analysis method based on Semi-Definite Programming to evaluate the modification of the bistable steady states induced by multiple parametric variations throughout bounded regions of the parameter space. Conclusions: Our analysis provides convincing evidence for the robustness, and hence plausibility, of the GAL regulatory network model. The proposed workflow also demonstrates the power of analytical methods from control theory to provide a direct quantitative characterization of the dynamics of multistable biomolecular regulatory systems without recourse to extensive computer simulations.