Multi-stable dynamics of the non-adiabatic repressilator.

The assumption of the fast binding of transcription factors (TFs) to promoters is a typical point in studies of synthetic genetic circuits functioning in bacteria. Although the assumption is effective for simplifying the models, it becomes questionable in the light of in vivo measurements of the times TF spends searching for its cognate DNA sites. We investigated the dynamics of the full idealized model of the paradigmatic genetic oscillator, the repressilator, using deterministic mathematical modelling and stochastic simulations. We found (using experimentally approved parameter values) that decreases in the TF binding rate changes the type of transition between steady state and oscillation. As a result, this gives rise to the hysteresis region in the parameter space, where both the steady state and the oscillation coexist. We further show that the hysteresis is persistent over a considerable range of the parameter values, but the presence of the oscillations is limited by the low rate of TF dimer degradation. Finally, the stochastic simulation of the model confirms the hysteresis with switching between the two attractors, resulting in highly skewed period distributions. Moreover, intrinsic noise stipulates trains of large-amplitude modulations around the stable steady state outside the hysteresis region, which makes the period distributions bimodal.