CONTROLLING the CELL CYCLE RESTRICTION SWITCH ACROSS the INFORMATION GRADIENT

Boolean models represent a drastic simplification of complex biomolecular systems, and yet accurately predict system properties, e.g., effective control strategies. Why is this? Parameter robustness has been highlighted as a general feature of biomolecular systems and may play an important role in the accuracy of Boolean models. We argue here that a useful way to view a system's controllability properties is through its repertoire of self-sustaining positive circuits (stable motifs). We examine attractor control and self-sustaining circuits within the cell cycle restriction switch, a bistable regulatory circuit that allows or prevents entry into the cell cycle. We explore this system using three models: a previously published Boolean model, a Hill kinetics model that we construct from the Boolean model using the HillCube methodology, and a reaction-based model we construct from the literature. We highlight the robustness of stable motifs across these three levels of modeling detail. We also show how consideration of control-robust regulatory circuits can aid in parameter specification.