Sensitivity Amplification in the Phosphorylation-Dephosphorylation Cycle: Nonequilibrium steady states, chemical master equation and temporal cooperativity

TL;DR

This paper investigates temporal cooperativity in phosphorylation-dephosphorylation cycles, revealing its mathematical equivalence to allosteric cooperativity and highlighting its potential for ultrasensitivity regulation.

Contribution

It provides a comprehensive analysis of temporal cooperativity, comparing it with allosteric cooperativity, and demonstrates its broader regulatory capacity for ultrasensitivity.

Findings

Temporal cooperativity is mathematically equivalent to allosteric cooperativity.

Ultrasensitivity depends on the total number of target molecules, not enzyme sites.

Chemical equilibrium abolishes sensitivity amplification.

Abstract

A new type of cooperativity termed temporal cooperativity [Biophys. Chem. 105 585-593 (2003), Annu. Rev. Phys. Chem. 58 113-142 (2007)], emerges in the signal transduction module of phosphorylation-dephosphorylation cycle (PdPC). It utilizes multiple kinetic cycles in time, in contrast to allosteric cooperativity that utilizes multiple subunits in a protein. In the present paper, we thoroughly investigate both the deterministic (microscopic) and stochastic (mesoscopic) models, and focus on the identification of the source of temporal cooperativity via comparing with allosteric cooperativity. A thermodynamic analysis confirms again the claim that the chemical equilibrium state exists if and only if the phosphorylation potential $\triangle G=0$, in which case the amplification of sensitivity is completely abolished. Then we provide comprehensive theoretical and numerical analysis with the first-order and zero-order assumptions in phosphorylation-dephosphorylation cycle respectively. Furthermore, it is interestingly found that the underlying mathematics of temporal cooperativity and allosteric cooperativity are equivalent, and both of them can be expressed by "dissociation constants", which also characterizes the essential differences between the simple and ultrasensitive PdPC switches. Nevertheless, the degree of allosteric cooperativity is restricted by the total number of sites in a single enzyme molecule which can not be freely regulated, while temporal cooperativity is only restricted by the total number of molecules of the target protein which can be regulated in a wide range and gives rise to the ultrasensitivity phenomenon.