Mechanism for the Generation of Robust Circadian Oscillations through Ultransensitivity and Differential Binding Affinity.

Agnish Kumar Behera,Clara Del Junco,Suriyanarayanan Vaikuntanathan

doi:10.1021/acs.jpcb.1c05915

Agnish Kumar Behera, Clara Del Junco + Show 1 more

Open Access

https://doi.org/10.1021/acs.jpcb.1c05915

Copy DOI

Abstract

Biochemical circadian rhythm oscillations play an important role in many signaling mechanisms. In this work, we explore some of the biophysical mechanisms responsible for sustaining robust oscillations by constructing a minimal but analytically tractable model of the circadian oscillations in the KaiABC protein system found in the cyanobacteria S. elongatus. In particular, our minimal model explicitly accounts for two experimentally characterized biophysical features of the KaiABC protein system, namely, a differential binding affinity and an ultrasensitive response. Our analytical work shows how these mechanisms might be crucial for promoting robust oscillations even in suboptimal nutrient conditions. Our analytical and numerical work also identifies mechanisms by which biological clocks can stably maintain a constant time period under a variety of nutrient conditions. Finally, our work also explores the thermodynamic costs associated with the generation of robust sustained oscillations and shows that the net rate of entropy production alone might not be a good figure of merit to asses the quality of oscillations.

Highlights

The KaiB proteins play no role in this ultrasensitive response
It was postulated in ref 17 that this ultrasensitive switch plays a central role in ensuring robust oscillations
The various biochemical states of the KaiABC protein are summarized in Figures 1 and 2

Summary

Introduction

We build on recent experimental and modeling work in ref 17 and show how a particular ultrasensitive switch in the KaiABC biochemical circuit can control the quality and robustness of oscillations. In ref 17, the authors identify a previously underappreciated ultrasensitive response in the phosphorylation levels of the KaiC proteins as the concentration of the KaiA proteins is tuned. The KaiB proteins play no role in this ultrasensitive response. It was postulated in ref 17 that this ultrasensitive switch plays a central role in ensuring robust oscillations. The ultrasensitive switch allows the system to exhibit sustained oscillations even at low levels of the energy rich molecule, ATP.[17] Motivated by this work, we build a minimal Markov state model that

Methods

Results

Discussion

Conclusion