On a stochastic approach to model the double phosphorylation/dephosphorylation cycle

Because of the unavoidable intrinsic noise affecting biochemical processes, a stochastic approach is usually preferred whenever a deterministic model gives a too rough information or, worse, may lead to erroneous qualitative behaviors and/or quantitative wrong results. In this work we focus on the Chemical Master Equation (CME)-based method which provides an accurate stochastic description of complex biochemical reaction networks in terms of probability distribution of the underlying chemical populations. Indeed, deterministic models can be dealt with as first-order approximations of the average values dynamics coming from the stochastic CME approach. Here we investigate the double phosphorylation/dephosphorylation cycle, a well-studied enzymatic reaction network where the inherent double time scale requires to exploit Quasi-Steady State Approximation (QSSA) approaches to infer qualitative and quantitative information. Within the deterministic realm, several researchers have deeply investigated the use of the proper QSSA, agreeing to highlight that only one type of QSSA (the total-QSSA) is able to faithfully replicate the qualitative behavior of bistability occurrences, as well as the correct assessment of the equilibrium points, accordingly to the not approximated (full) model. Based on recent results providing CME solutions that do not resort to Monte Carlo simulations, the proposed stochastic approach shows some counterintuitive facts arising when trying to straightforwardly transfer bistability deterministic results into the stochastic realm, and suggests how to handle such cases according to both theoretical and numerical results.