Chorasiya, G. | Search bioRxiv

bioRxiv2026

A Structural Design Principle for Temperature Robustness in Biomolecular Circuits

The dominant paradigm for temperature robustness in biomolecular circuits is for the parameters to be tuned to have matching temperature dependencies so that their overall effect cancels out. This contrasts with the robustness due to circuit structure, typically operative in circuits where robustness to a single input parameter is desired. The importance of the circuit structure in temperature robustness is generally unclear. We addressed this issue in a benchmark negative feedback circuit using a combination of theoretical modelling and experimental measurements. We found that the response to a temperature perturbation in a model of negative feedback was qualitatively different from the response in a model without feedback. We experimentally measured the response of the negative feedback circuit to a temperature perturbation and found that it was smaller than that of the circuit without feedback, in line with the theoretical finding. We confirmed this theoretical prediction experimentally. The initial response of the negative feedback circuit, paradoxically, was larger than the circuit without feedback. The resolution of this paradox was in accounting for the faster dynamics in the negative feedback circuit. These results show a simple design principle of temperature robustness that can operate in a widespread circuit motif and may also apply to other perturbations which, like temperature, affect multiple parameters simultaneously.

systems biology↗

bioRxiv2025

Robustness of a Bistable Biomolecular PositiveFeedback Circuit to Global Parametric Perturbations

Achieving robustness to multi-parametric perturbations where all parameters can change at the same time is challenging because the controller would also face the same disturbance as the plant. For nonlinear positive feedback, an important mechanism for cell fate determination in biomolecular contexts, quantitative aspects of robustness to such perturbations are generally unclear. Here we used mathematical methods of control and dynamical systems, interval analysis, and a benchmark model of a bistable biomolecular positive feedback circuit to address this. We confirmed that such perturbations can change the qualitative behaviour of the system extinguishing bistability. We obtained a quantitative relation between the relative variation in the stable steady state and the unstable steady state in terms of the relative changes in the parameters. We showed how the deviation in the trajectories near the unstable steady state due to multi-parametric perturbations could diverge almost exponentially after an initial transient, which could have a significant impact on the bistable switching dynamics. We found that the size of the eigenvalue for the unstable steady state was greater than that for the stable steady state, and proved this for certain parameters using a rigorous numerical construction. We noted a tradeoff between enhancing the parameter space of bistability and the increased sensitivity in the bistable dynamics due to parametric perturbations. We obtained rigorous bounds on the entire transient response for multi-parametric perturbations. These results provide a quantitative insight into the robustness of a bistable biomolecular positive feedback circuit to multi-parametric perturbations.

systems biology↗