An all-encompassing global convergence result for processive multisite phosphorylation systems

Phosphorylation, the enzyme-mediated addition of a phosphate group to a molecule, is a ubiquitous chemical mechanism in biology. Multisite phosphorylation, the addition of phosphate groups to multiple sites of a single molecule, may be distributive or processive. Distributive systems, which require an enzyme and substrate to bind several times in order to add multiple phosphate groups, can be bistable. Processive systems, in contrast, require only one binding to add all phosphate groups, and were recently shown to be globally stable. However, this global convergence result was proven only for a specific mechanism of processive phosphorylation/dephosphorylation (namely, all catalytic reactions are reversible). Accordingly, we generalize this result to allow for processive phosphorylation networks in which each reaction may be irreversible, and also to account for possible product inhibition. We accomplish this by first defining an all-encompassing processive network that encapsulates all of these schemes, and then appealing to recent results of Marcondes de Freitas et al. that assert global convergence by way of monotone systems theory and network/graph reductions (corresponding to removing intermediate complexes). Our results form a case study into the question of when global convergence is preserved when reactions and/or intermediate complexes are added to or removed from a network.