Stabilisation of Antithetic Control via Molecular Buffering

Abstract

A key goal in synthetic biology is the construction of molecular circuits that robustly adapt to perturbations. Although many natural systems display perfect adaptation, whereby stationary molecular concentrations are insensitive to perturbations, its de novo engineering has proven elusive. The discovery of the antithetic control motif was a significant step toward a universal mechanism for engineering perfect adaptation. Antithetic control provides perfect adaptation in a wide range of systems, but it can lead to oscillatory dynamics due to loss of stability, and moreover, it can lose perfect adaptation in fast growing cultures. Here, we introduce an extended antithetic control motif that resolves these limitations. We show that molecular buffering, a widely conserved mechanism for homeostatic control in nature, stabilises oscillations and allows for near-perfect adaptation during rapid growth. We study multiple buffering topologies and compare their performance in terms of their stability and adaptation properties. We illustrate the benefits of our proposed strategy in exemplar models for biofuel production and growth rate control in bacterial cultures. Our results provide an improved circuit for robust control of biomolecular systems.

Stabilization of antithetic control via molecular buffering

“…All scripts used in this study are openly accessible through . The data are provided in the electronic supplementary material [40].…”

Regulation strategies for two-output biomolecular networks

“…The efficacy of this biomolecular mechanism has also been demonstrated experimentally in living cells, at both the cell population and the single-cell level, and in cell-free environments using either external (in silico) or embedded single-output control schemes [33,39,40,43,[55][56][57][58][59][60][61]. Furthermore, in recent years, considerable attention has been given to topologies combining the antithetic integral controller with proportional and derivative control action or biomolecular buffering [39,40,43,60,[62][63][64][65][66]. Such efforts seek to resolve commonly encountered issues associated with the standalone antithetic integral controller, such as instability, poor transient dynamics including overshoots, and long-lasting oscillations or increased variance.…”