A symmetric dual feedback system provides a robust and entrainable oscillator

Area of Science:

• * Chronobiology and molecular biology.
• * Systems biology and evolutionary modeling.

Background:

• * Circadian clocks in organisms rely on molecular mechanisms, often involving transcriptional-translational feedback loops, to maintain daily cycles.
• * While single feedback loops suffice for oscillations, complex circadian networks utilize multiple loops, influencing rhythm robustness and entrainment.
• * The evolutionary advantage of complex feedback systems remains an area of investigation.

Purpose of the Study:

• * To quantitatively assess the robustness and light entrainment of four distinct circadian clock feedback models: single, semi-dual, dual, and redundant.
• * To identify the most effective feedback architecture for robust and entrainable circadian oscillations.
• * To elucidate the evolutionary mechanisms favoring specific feedback system designs.

Main Methods:

• * Employed a two-phase search (TPS) method for efficient and unbiased exploration of kinetic parameter spaces generating circadian oscillations.
• * Utilized quasi-multiparameter sensitivity (QMPS) to rapidly and accurately measure the robustness of models to parameter uncertainties.
• * Analyzed four competing feedback models (single, semi-dual, dual, redundant) by searching all plausible kinetic parameter sets.

Main Results:

• * Challenged the prevailing hypothesis that redundant feedback models are the most robust circadian oscillators.
• * Identified the dual feedback model as the most robust to parameter perturbations and the most effective at entraining to diverse light-dark cycles.
• * Discovered that kinetic symmetry within dual loops and their coupling via protein complexes are crucial for robust and entrainable oscillations.

Conclusions:

• * The dual feedback model, prevalent in biological systems, offers superior robustness and entrainability compared to other architectures.
• * Kinetic symmetry and protein complex coupling are key evolutionary drivers for robust circadian clock function.
• * This study provides insights into the evolution of complex feedback systems in circadian clocks.