Monostationarity and Multistationarity in Tree Networks of Goldbeter-Koshland Loops.

A major challenge in systems biology is to elicit general properties in the face of molecular complexity. Here, we introduce a class of enzyme-catalysed biochemical networks and examine how the existence of a single positive steady state (monostationarity) depends on the network structure, enzyme mechanisms, kinetic rate laws and parameter values. We consider Goldbeter-Koshland (GK) covalent modification loops arranged in a tree network, so that a substrate form in one loop can be an enzyme in another loop. GK loops are a canonical motif in cell signalling and trees offer a generalisation of linear cascades which accommodate network complexity while remaining mathematically tractable. In particular, they permit a modular, recursive proof strategy which may be more widely applicable. We show that if each enzyme follows its own complex reaction mechanism under mass action kinetics, then any network is monostationary for all appropriate parameter values. If the kinetics is non-mass action with a plausible monotonicity requirement, and each enzyme follows the Michaelis-Menten mechanism, then monostationarity is preserved. Surprisingly, a single GK loop with a complex enzyme mechanism under non-mass action monotone kinetics can have more than one positive steady state (multistationarity). The broader interplay between network structure, enzyme mechanism and kinetics remains an intriguing open problem.