Thermodynamic bounds on ultrasensitivity in covalent switching

Switch-like motifs are among the basic building blocks of biochemical networks. A common motif that can serve as an ultrasensitive switch consists of two enzymes acting antagonistically on a substrate, one making and the other removing a covalent modification. To work as a switch, such covalent modification cycles must be held out of thermodynamic equilibrium by continuous expenditure of energy. Here, we exploit the linear framework for timescale separation to establish tight bounds on the performance of any covalent-modification switch in terms of the chemical potential difference driving the cycle. The bounds apply to arbitrary enzyme mechanisms, not just Michaelis-Menten, with arbitrary rate constants and thereby reflect fundamental phys-ical constraints on covalent switching.

Automated summary

Switch-like motifs, particularly ultrasensitive switches, which consist of two enzymes acting antagonistically on a substrate by making or removing a covalent modification, play important roles in biochemical networks. In this study, the linear framework for timescale separation was used to establish strict bounds on the performance of any covalent-modification switch in terms of the chemical potential difference driving the cycle. These bounds apply to different enzyme mechanisms and rate constants, providing fundamental physical constraints on covalent switching.