Thermodynamic bounds on ultrasensitivity in covalent switching

TL;DR

This paper derives fundamental thermodynamic bounds on the performance of covalent modification switches in biochemical networks, highlighting physical constraints on their ultrasensitivity.

Contribution

It establishes universal bounds on covalent switch performance based on thermodynamics, applicable to arbitrary enzyme mechanisms and rate constants.

Findings

Bounds depend on the chemical potential difference driving the cycle.

Performance limits are fundamental and not dependent on specific enzyme mechanisms.

The framework applies to arbitrary enzyme kinetics, not just Michaelis-Menten.

Abstract

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 physical constraints on covalent switching.