Circadian rhythms are generated by self-sustaining biochemical oscillators that are capable of maintaining a period close to 24 hours over a wide range of conditions. The cyanobacteria have the simplest known circadian clock, and the core mechanism that generates oscillations can be reconstituted in a test tube using three purified components, the proteins KaiA, KaiB, and KaiC. This oscillator-in-a-tube displays remarkably robust rhythms in the face of changes in protein concentrations and temperature. Further, the oscillator is able to respond sensitively to metabolic input signals in a manner similar to the clock of the intact cell.
I will describe our combined experimental and mathematical modeling efforts to understand the mechanisms underlying robust performance and coupling of the oscillator to metabolism by studying the properties of the two catalytic domains in the clock protein KaiC. I will present a model where the circadian clock balances input responsiveness and robust timing by coupling together slow enzymatic reactions that have differential sensitivity to input signals.