Switch-like behaviours in biochemical networks are of fundamental significance in biological signal processing, and exist as two distinct types: ultra-sensitivity and bistability. Here we propose two new models of a reversible covalent-modification cycle with positive autoregulation (PAR), a motif structure that is thought to be capable of both ultrasensitivity and bistability in different parameter regimes. These new models appeal to a modelling framework that we call complex-complete, which accounts fully for the molecular complexities of the underlying signalling mechanisms. Each of the two new models encodes a specific molecular mechanism for PAR. We demonstrate that the modelling simplifications for PAR models that have been used in previous work, which rely on Michaelian approximations, are unable to accurately recapitulate the qualitative signalling responses supported by our detailed models. Strikingly, we show that complex-complete PAR models are capable of new qualitative responses such as one-way switches and a ‘prozone’ effect, depending on the specific PAR-encoding mechanism, which are not supported by Michaelian simplifications. Our results highlight the critical importance of accurately representing the molecular details of biochemical signalling mechanisms, and strongly suggest that the Michaelian approximation is inadequate for predictive models of enzyme-mediated chemical reactions with added regulations such as PAR.

生化网络中的类开关行为在生物信号处理中具有重要意义，并以两种不同的类型存在：超灵敏度和双稳态。在这里，我们提出了两种具有正向自动调节 (PAR) 的可逆共价修饰循环的新模型，这种基序结构被认为能够在不同的参数范围内具有超敏感性和双稳态。这些新模型吸引了我们称之为复杂完整的建模框架，这完全解释了潜在信号机制的分子复杂性。这两个新模型中的每一个都编码了 PAR 的特定分子机制。我们证明，在以前的工作中使用的 PAR 模型的建模简化依赖于 Michaelian 近似，无法准确地概括我们详细模型支持的定性信号响应。引人注目的是，我们表明，复杂完整的 PAR 模型能够产生新的定性响应，例如单向开关和“前带”效应，具体取决于特定的 PAR 编码机制，这些机制不受 Michaelian 简化的支持。我们的结果强调了准确表示生化信号机制的分子细节的重要性，