Bistability in the Chemical Master Equation for Dual Phosphorylation Cycles

TL;DR

This paper investigates the stochastic behavior of dual phosphorylation cycles using the Chemical Master Equation, revealing how fluctuations influence bistability and providing explicit solutions under certain conditions.

Contribution

It offers a novel analysis of the stationary distribution in dual phosphorylation cycles, especially under non-equilibrium conditions, using Helmholtz decomposition and perturbative methods.

Findings

Explicit equilibrium distributions when detailed balance holds

Stationary non-equilibrium states influenced by chemical fluxes

Bistability characterized by transition rates and Fokker-Planck approximation

Abstract

Dual phospho/dephosphorylation cycles, as well as covalent enzymatic-catalyzed modifications of substrates, are widely diffused within cellular systems and are crucial for the control of complex responses such as learning, memory and cellular fate determination. Despite the large body of deterministic studies and the increasing work aimed to elucidate the effect of noise in such systems, some aspects remain unclear. Here we study the stationary distribution provided by the two-dimensional Chemical Master Equation for a well known model of a two step phospho/dephosphorylation cycle using the quasi steady state approximation of the enzymatic kinetics. Our aim is to analyze the role of fluctuations and the molecules distribution properties in the transition to a bistable regime. When detailed balance conditions are satisfied it is possible to compute equilibrium distributions in a closed and explicit form. When detailed balance is not satisfied, the stationary non-equilibrium state is strongly influenced by the chemical fluxes. In the last case, we show how the Helmholtz decomposition of the external field associated to the generation and recombination transition rates, into a conservative and a rotational (irreversible) part, allows to compute the stationary distribution via a perturbative approach . For a finite number of molecules, there exists diffusion dynamics in a macroscopic region of the state space, where a relevant transition rate between the two critical points is observed. Further, the stationary distribution function can be approximated by the solution of a Fokker-Planck equation. We illustrate the theoretical results using several numerical simulations.