bioRxiv2017
The antithetic integral feedback motif recently introduced in [6] is known to ensure robust perfect adaptation for the mean dynamics of a given molecular species involved in a complex stochastic biomolecular reaction network. However, it was observed that it also leads to a higher variance in the controlled network than that obtained when using a constitutive (i.e. open-loop) control strategy. This was interpreted as the cost of the adaptation property and may be viewed as a performance deterioration for the overall controlled network. To decrease this variance and improve the performance, we propose to combine the antithetic integral feedback motif with a negative feedback strategy. Both theoretical and numerical results are obtained. The theoretical ones are based on a tailored moment closure method allowing one to obtain approximate expressions for the stationary variance for the controlled network and predict that the variance can indeed be decreased by increasing the strength of the negative feedback. Numerical results verify the accuracy of this approximation and show that the controlled species variance can indeed be decreased, sometimes below its constitutive level. Three molecular networks are considered in order to verify the wide applicability of two types of negative feedback strategies. The main conclusion is that there is a trade-off between the speed of the settling-time of the mean trajectories and the stationary variance of the controlled species; i.e. smaller variance is associated with larger settling-time.\n\nAuthor summaryHomeostasis, the ability of living organisms to regulate their internal state, is of fundamental importance for their adaptation to environmental changes and their survival. This is the reason why complex regulatory genetic networks evolved and allowed for the emergence of more and more complex organisms. Recently, the theoretical study of those regulatory networks using ideas and concepts from control theory and the design of novel ones have gained a lot of attention. Synthetic regulatory circuits are seen as elementary building blocks for the design of complex networks that need to incorporate some regulating elements to be fully functional. This is for instance the case in metabolic engineering where the production of biomolecules, such as drugs or biofuels, need to be optimized and tightly regulated. A particular circuit, the so-called antithetic integral controller, is now known to ensure homeostasis even when regulatory circuits are subject to randomness. However, it is also known that this circuit increases variability in the network. The effects of a correcting negative feedback loop on the variance are discussed here and it is shown that variability can be reduced this way. Notably, we show that there is a tradeoff between speed of the network and variability.