Life on Earth depends on chemical communication and the ability of biomolecular switches to integrate various chemical signals that trigger their activation or deactivation over time scales ranging from microseconds to days. The ability to similarly program and control the kinetics of artificial switches would greatly assist the design and optimization of future chemical and nanotechnological systems. Two distinct structure-switching mechanisms are typically employed by biomolecular switches: induced fit (IF) and conformational selection (CS). Despite 60 years of experimental and theoretical investigations, the kinetic and evolutive advantages of these two mechanisms remain unclear. Here, we have created a simple modular DNA switch that can operate through both mechanisms and be easily tuned and adapted to characterize its thermodynamic and kinetic parameters. We show that the fastest activation rate of a switch occurs when the ligand is able to bind its inactive conformation (IF). In contrast, we show that when the ligand can only bind the active conformation of the switch (CS), its activation rate can be easily programmed over many orders of magnitude by a simple tuning of its conformational equilibrium. We demonstrate the programming ability of both these mechanisms by designing a drug delivery vessel that can be programmed to release a drug over different time scales (>1000-fold). Overall, these findings provide a programmable strategy to optimize the kinetics of molecular systems and nanomachines while also illustrating how evolution may have taken advantage of IF and CS mechanisms to optimize the kinetics of biomolecular switches.

中文翻译：

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化学通讯动力学编程：诱导拟合与构象选择


地球上的生命依赖于化学通讯和生物分子开关整合各种化学信号的能力，这些信号在从微秒到几天的时间尺度上触发它们的激活或失活。同样编程和控制人工开关动力学的能力将极大地有助于未来化学和纳米技术系统的设计和优化。生物分子开关通常采用两种不同的结构转换机制：诱导拟合 （IF） 和构象选择 （CS）。尽管进行了 60 年的实验和理论研究，但这两种机制的动力学和进化优势仍不清楚。在这里，我们创建了一个简单的模块化 DNA 开关，它可以通过两种机制进行操作，并且可以轻松调整和调整以表征其热力学和动力学参数。我们表明，当配体能够结合其无活性构象 （IF） 时，开关的最快激活率就会出现。相比之下，我们表明，当配体只能结合开关的活性构象 （CS） 时，通过简单地调整其构象平衡，可以很容易地在许多数量级上编程其激活速率。我们通过设计一个药物输送容器来证明这两种机制的编程能力，该容器可以被编程为在不同时间尺度 （>1000 倍） 上释放药物。总体而言，这些发现提供了一种可编程的策略来优化分子系统和纳米机器的动力学，同时也说明了进化如何利用 IF 和 CS 机制来优化生物分子开关的动力学。