Design principles for enhancing phase sensitivity and suppressing phase fluctuations simultaneously in biochemical oscillatory systems

Biological systems need to function accurately in the presence of strong noise and at the same time respond sensitively to subtle external cues. Here we study design principles in biochemical oscillatory circuits to achieve these two seemingly incompatible goals. We show that energy dissipation can enhance phase sensitivity linearly by driving the phase-amplitude coupling and increase timing accuracy by suppressing phase diffusion. Two general design principles in the key underlying reaction loop formed by two antiparallel pathways are found to optimize oscillation performance with a given energy budget: balancing the forward-to-backward flux ratio between the two pathways to reduce phase diffusion and maximizing the net flux of the phase-advancing pathway relative to that of the phase-retreating pathway to enhance phase sensitivity. Experimental evidences consistent with these design principles are found in the circadian clock of cyanobacteria. Future experiments to test the predicted dependence of phase sensitivity on energy dissipation are proposed.