Repressilator with time-delayed gene expression. Part II. Stochastic description

The repressilator is the first genetic regulatory network in synthetic biology, which was artificially constructed in 2000. It is a closed network of three genetic elements $lacI$, $\lambda cI$ and $tetR$, which have a natural origin, but are not found in nature in such a combination. The promoter of each of the three genes controls the next cistron via the negative feedback, suppressing the expression of the neighboring gene. In our previous paper [Bratsun et al., 2018], we proposed a mathematical model of a delayed repressillator and studied its properties within the framework of a deterministic description. We assume that delay can be both natural, i.e. arises during the transcription / translation of genes due to the multistage nature of these processes, and artificial, i.e. specially to be introduced into the work of the regulatory network using gene engineering technologies. In this work, we apply the stochastic description of dynamic processes in a delayed repressilator, which is an important addition to deterministic analysis due to the small number of molecules involved in gene regulation. The stochastic study is carried out numerically using the Gillespie algorithm, which is modified for time delay systems. We present the description of the algorithm, its software implementation, and the results of benchmark simulations for a one-gene delayed autorepressor. When studying the behavior of a repressilator, we show that a stochastic description in a number of cases gives new information about the behavior of a system, which does not reduce to deterministic dynamics even when averaged over a large number of realizations. We show that in the subcritical range of parameters, where deterministic analysis predicts the absolute stability of the system, quasi-regular oscillations may be excited due to the nonlinear interaction of noise and delay. Earlier, we have discovered within the framework of the deterministic description, that there exists a long-lived transient regime, which is represented in the phase space by a slow manifold. This mode reflects the process of long-term synchronization of protein pulsations in the work of the repressilator genes. In this work, we show that the transition to the cooperative mode of gene operation occurs a two order of magnitude faster, when the effect of the intrinsic noise is taken into account. We have obtained the probability distribution of moment when the phase trajectory leaves the slow manifold and have determined the most probable time for such a transition. The influence of the intrinsic noise of chemical reactions on the dynamic properties of the repressilator is discussed.