The phosphate economy in cells is essential in many biochemical processes from signal transduction, to energy metabolism to DNA and RNA synthesis. All living systems therefore acquire and regulate phosphate in order to survive and reproduce. E. coli, for example, regulate the inorganic phosphate (Pi) uptake in order to survive under phosphate-limiting conditions. To achieve this, E. coli have developed an accurate control mechanism, Pho regulon, to adapt to environmental perturbations of Pi, controlled by the PhoR/PhoB two-component regulatory system (TCS). The signalling of the TCS is delivered by interactions with the ABC transporter via PhoU. However, the exact mechanisms of interaction are unknown. Here, we propose mechanistic explanations for these mechanisms via a quantitative computational analysis, whereby we model plausible ABC and TCS state transitions. We analyse the interaction mechanism and the dynamic behaviour of TCS system deactivation in relation to the external Pi levels. We show that the behaviour of this system depends on the network structure. In particular, we use alternative models to demonstrate that variation in interaction patterns affect the response time of the system. Overall we show how to model a system where some key interactions are as yet unknown and to provide testable predictions that can easily be verified in the lab. This way, modelling is being used to increase our mechanistic understanding of important biological systems by defining and driving wet lab experiments and to increase our biological understanding of the often complex relationship between an organism and its environment.

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