Mathematical models can enable a predictive understanding of mechanism in cell biology by quantitatively describing complex networks of interactions, but such models are often poorly constrained by available data. Owing to its relative biochemical simplicity, the core circadian oscillator in Synechococcus elongatus has become a prototypical system for studying how collective dynamics emerge from molecular interactions. The oscillator consists of only three proteins, KaiA, KaiB, and KaiC, and near‐24‐h cycles of KaiC phosphorylation can be reconstituted in vitro . Here, we formulate a molecularly detailed but mechanistically naive model of the KaiA—KaiC subsystem and fit it directly to experimental data within a Bayesian parameter estimation framework. Analysis of the fits consistently reveals an ultrasensitive response for KaiC phosphorylation as a function of KaiA concentration, which we confirm experimentally. This ultrasensitivity primarily results from the differential affinity of KaiA for competing nucleotide‐bound states of KaiC. We argue that the ultrasensitive stimulus–response relation likely plays an important role in metabolic compensation by suppressing premature phosphorylation at nighttime.

中文翻译：

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贝叶斯模型揭示了蓝藻生物钟中代谢物依赖性的超敏感性。


数学模型可以通过定量描述复杂的相互作用网络来预测性地理解细胞生物学的机制，但此类模型通常很难受到可用数据的约束。由于其相对生化简单，细长聚球藻的核心昼夜节律振荡器已成为研究分子相互作用如何产生集体动力学的典型系统。该振荡器仅由三种蛋白质组成：KaiA、KaiB 和 KaiC，KaiC 磷酸化的近 24 小时周期可以在体外重建。在这里，我们制定了 KaiA-KaiC 子系统的分子详细但机械上朴素的模型，并将其直接拟合到贝叶斯参数估计框架内的实验数据。拟合分析一致揭示了 KaiC 磷酸化作为 KaiA 浓度函数的超灵敏响应，我们通过实验证实了这一点。这种超敏感性主要是由于 KaiA 与 KaiC 的竞争性核苷酸结合状态的不同亲和力造成的。我们认为，超敏感的刺激-反应关系可能通过抑制夜间过早磷酸化在代谢补偿中发挥重要作用。