Loads Bias Bistable Switches in Synthetic and Natural Systems

Abstract

A traditional view of biological modules is that they operate the same in the presence and absence of downstream targets including gene promoters and other proteins. Recent theoretical work [1] suggests that this may not be the case and the properties of biochemical networks are affected by the interactions that the output of the network has with downstream elements. Downstream components can change the dynamic and static properties of the upstream circuit without explicit feedback. Understanding the properties of network modules connected in different ways to downstream components is therefore necessary before we can reliably use these modules as parts of larger synthetic biology circuits. Bistable circuits play an important role in both natural and synthetic biology. using computer modeling and simulations, we study a variety of bistable circuits including the synthetic genetic toggle switch under the action of a downstream binding element (a “load”). We find that the load can have profound effects on the dynamic properties of the network, significantly affecting the ability of the system to switch from one state to another. Construction of an energy landscape picture using stochastic simulations show that loads significantly bias the bistable switch towards one state. Surprisingly in the genetic toggle switch this effect is particularly strong when the load is on the other state. This is a simple but novel way of tuning bistable protein circuits in synthetic biology and may be ubiquitous in natural systems.[1] Del Vecchio, D., A.J. Ninfa, and E.D. Sontag, Modular cell biology: retroactivity and insulation. Mol Syst Biol, 2008. 4: p. 161.