Singularly perturbed monotone systems and an Application to double phosphorylation cycles (Q1015419)

The behavior of a strongly monotone dynamical system is determined by the generic convergence theorem due to M. Hirsch: almost every bounded solution converges to the set of equilibria. Monotone systems are particularly useful in biochemical applications, but not all models in that area are monotone systems. The main goal of the authors is to show that there is a special class of dynamical systems, namely the class of singularly perturbed dynamical systems \[ \frac{dx}{dt}= f_0(x,y, \varepsilon),\quad \varepsilon\frac{dy}{dt}=g_0(x,y,\varepsilon) \] which behave under some additional conditions for sufficiently small \(\varepsilon\) like a monotone system. The proof of this important fact is based on geometric singular perturbation theory (existence of slow invariant manifold). A consequence of this result is that systems containing negative feedback loops on a sufficiently fast time scale can behave like monotone systems. (In a monotone system, every net feedback loop is positive.) The authors demonstrate this fact by means of a double-phosphorylation ``futile cycle'' motif playing a central role in eukariotic cell signaling.