A novel interaction perturbation analysis reveals a comprehensive regulatory principle underlying various biochemical oscillators

Jun Hyuk Kang, Kwang-Hyun Cho

Biochemical oscillations play an important role in maintaining physiological and cellular homeostasis in biological systems. The frequency and amplitude of oscillations are regulated to properly adapt to environments by numerous interactions within biomolecular networks. Despite the advances in our understanding of biochemical oscillators, the relationship between the network structure of an oscillator and its regulatory function still remains unclear. To investigate such a relationship in a systematic way, we have developed a novel analysis method called interaction perturbation analysis that enables direct modulation of the strength of every interaction and evaluates its consequence on the regulatory function. We have applied this new method to the analysis of three representative types of oscillators. The results of interaction perturbation analysis showed different regulatory features according to the network structure of the oscillator: (1) both frequency and amplitude were seldom modulated in simple negative feedback oscillators; (2) frequency could be tuned in amplified negative feedback oscillators; (3) amplitude could be modulated in the incoherently amplified negative feedback oscillators. A further analysis of naturally-occurring biochemical oscillator models supported such different regulatory features according to their network structures. Our results provide a clear evidence that different network structures have different regulatory features in modulating the oscillation frequency and amplitude. Our findings may help to elucidate the fundamental regulatory roles of network structures in biochemical oscillations.