A thermodynamically consistent model of the post-translational Kai circadian clock

Area of Science:

• Biochemistry
• Systems Biology
• Statistical Mechanics

Background:

• The cyanobacterial circadian clock relies on the KaiA, KaiB, and KaiC protein system.
• KaiC's phosphorylation cycle is central, but its thermodynamic underpinnings remain unclear.

Purpose of the Study:

• To develop a thermodynamically consistent, statistical-mechanical model of the Kai-protein circadian clock.
• To elucidate the thermodynamic driving forces and timing mechanisms of the clock.

Main Methods:

• Developed a novel statistical-mechanical model incorporating ATP hydrolysis and phosphorylation.
• Employed a kinetic Monte Carlo algorithm to simulate over a billion reactions.

Main Results:

• ATP hydrolysis in KaiC's CI domain drives conformational changes, providing the clock's thermodynamic force.
• CII domain phosphorylation acts as the timer, regulating CI domain hydrolysis.
• The model explains KaiA's role in stimulating phosphorylation and its differential affinity for KaiC phosphoforms.

Conclusions:

• The model successfully describes experimental data and provides a unified thermodynamic explanation for the circadian clock.
• Highlights the interplay between ATP hydrolysis, phosphorylation, and protein-protein interactions in circadian timing.