How organisms are able to maintain robust homeostasis has in recent years received increased attention by the use of combined control engineering and kinetic concepts, which led to the discovery of robust controller motifs. While these motifs employ kinetic conditions showing integral feedback and homeostasis for step-wise perturbations, the motifs’ performance differ significantly when exposing them to time dependent perturbations. One type of controller motifs which are able to handle exponentially and even hyperbolically growing perturbations are based on derepression. In these controllers the compensatory reaction, which neutralizes the perturbation, is derepressed, i.e. its reaction rate is increased by the decrease of an inhibitor acting on the compensatory flux. While controllers in this category can deal well with different time-dependent perturbations they have the disadvantage that they break down once the concentration of the regulatory inhibitor becomes too low and the compensatory flux has gained its maximum value. We wondered whether it would be possible to bypass this restriction, while still keeping the advantages of derepression kinetics. In this paper we show how the inclusion of multisite inhibition and the presence of positive feedback loops lead to an amplified controller which is still based on derepression kinetics but without showing the breakdown due to low inhibitor concentrations. By searching for the amplified feedback motif in natural systems, we found it as a part of the plant circadian clock where it is highly interlocked with other feedback loops.

How organisms are able to maintain robust homeostasis has in recent years received increased attention by the use of combined control engineering and kinetic concepts, which led to the discovery of robust controller motifs. While these motifs employ kinetic conditions showing integral feedback and homeostasis for step-wise perturbations, the motifs' performance differ significantly when exposing them to time dependent perturbations. One type of controller motifs which are able to handle exponentially and even hyperbolically growing perturbations are based on derepression. In these controllers the compensatory reaction, which neutralizes the perturbation, is derepressed, i.e. its reaction rate is increased by the decrease of an inhibitor acting on the compensatory flux. While controllers in this category can deal well with different time-dependent perturbations they have the disadvantage that they break down once the concentration of the regulatory inhibitor becomes too low and the compensatory flux has gained its maximum value. We wondered whether it would be possible to bypass this restriction, while still keeping the advantages of derepression kinetics. In this paper we show how the inclusion of multisite inhibition and the presence of positive feedback loops lead to an amplified controller which is still based on derepression kinetics but without showing the breakdown due to low inhibitor concentrations. By searching for the amplified feedback motif in natural systems, we found it as a part of the plant circadian clock where it is highly interlocked with other feedback loops.