The receptor binding domain (RBD) of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) spike protein must undergo a crucial conformational transition to invade human cells. It is intriguing that this transition is accompanied by a synchronized movement of the entire spike protein. Therefore, it is possible to design allosteric regulators targeting non‐RBD but hindering the conformational transition of RBD. To understand the allosteric mechanism in detail, we establish a computational framework by integrating coarse‐grained molecular dynamic simulations and a state‐of‐the‐art neural network model called neural relational inference. Leveraging this framework, we have elucidated the allosteric pathway of the SARS‐CoV‐2 spike protein at the residue level and identified the molecular mechanisms involved in the transmission of allosteric signals. The movement of D614 is coupled with that of Q321. This interaction subsequently influences the movement of K528/K529, ultimately coupling with the movement of RBD during conformational changes. Mutations that weaken the interactions within this pathway naturally block the allosteric signal transmission, thereby modulating the conformational transitions. This observation also offers a rationale for the distinct allosteric patterns observed in the SARS‐CoV spike protein. Our result provides a useful method for analyzing the dynamics of potential viral variants in the future.

中文翻译：

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通过神经关系推理鉴定 SARS 和 SARS-CoV-2 刺突蛋白的变构途径

严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 刺突蛋白的受体结合域 (RBD) 必须经历关键的构象转变才能侵入人体细胞。有趣的是，这种转变伴随着整个刺突蛋白的同步运动。因此，可以设计针对非RBD但阻碍RBD构象转变的变构调节剂。为了详细了解变构机制，我们通过集成粗粒度分子动力学模拟和称为神经关系推理的最先进的神经网络模型建立了一个计算框架。利用这个框架，我们在残基水平上阐明了 SARS-CoV-2 刺突蛋白的变构途径，并确定了参与变构信号传递的分子机制。D614的机芯与Q321的机芯耦合。这种相互作用随后影响 K528/K529 的运动，最终在构象变化期间与 RBD 的运动耦合。削弱该途径内相互作用的突变自然会阻断变构信号传递，从而调节构象转变。这一观察结果还为 SARS-CoV 刺突蛋白中观察到的独特变构模式提供了理论依据。我们的结果为分析未来潜在病毒变异的动态提供了一种有用的方法。