Multi-stable dynamics of the non-adiabatic repressilator

Area of Science:

• Synthetic biology
• Biophysics
• Systems biology

Background:

• The fast binding of transcription factors (TFs) to promoters is a common assumption in synthetic genetic circuit modeling.
• In vivo measurements suggest TF search times can be significant, questioning this assumption.

Purpose of the Study:

• To investigate the dynamics of the repressilator genetic oscillator model considering realistic TF binding rates.
• To analyze the impact of TF binding kinetics on the transition between steady states and oscillations.

Main Methods:

• Deterministic mathematical modeling of the repressilator circuit.
• Stochastic simulations to explore system dynamics and noise effects.
• Utilized experimentally validated parameter values.

Main Results:

• Decreased TF binding rates alter the transition dynamics, leading to a hysteresis region where steady state and oscillation coexist.
• Hysteresis is robust across a range of parameters, but oscillations are limited by TF dimer degradation rates.
• Stochastic simulations confirm hysteresis and reveal skewed period distributions due to attractor switching and noise-induced modulations.

Conclusions:

• Realistic TF binding kinetics are crucial for accurately modeling synthetic genetic circuits like the repressilator.
• The identified hysteresis phenomenon has significant implications for the design and predictability of genetic oscillators.
• Intrinsic noise plays a key role in shaping the system's behavior, particularly outside the hysteresis region.