In the innate immune system, the host defense from the invasion of external pathogens triggers the inflammatory responses. Proteins involved in the inflammatory pathways were often found to aggregate into supramolecular oligomers, called 'inflammasome', mostly through the homotypic interaction between their domains that belong to the death domain superfamily. Although much has been known about the formation of these helical molecular machineries, the detailed correlation between the dynamics of their assembly and the structure of each domain is still not well understood. Using the filament formed by the PYD domains of adaptor molecule ASC as a test system, we constructed a new multiscale simulation framework to study the kinetics of inflammasome assembly. We found that the filament assembly is a multi-step, but highly cooperative process. Moreover, there are three types of binding interfaces between domain subunits in the ASCPYD filament. The multiscale simulation results suggest that dynamics of domain assembly are rooted in the primary protein sequence which defines the energetics of molecular recognition through three binding interfaces. Interface I plays a more regulatory role than the other two in mediating both the kinetics and the thermodynamics of assembly. Finally, the efficiency of our computational framework allows us to design mutants on a systematic scale and predict their impacts on filament assembly. In summary, this is, to the best of our knowledge, the first simulation method to model the spatial-temporal process of inflammasome assembly. Our work is a useful addition to a suite of existing experimental techniques to study the functions of inflammasome in innate immune system.

中文翻译：

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多尺度模拟揭示了炎性体组装的动力学机制。

在先天免疫系统中，宿主抵抗外部病原体入侵的防御触发了炎症反应。通常发现参与炎症途径的蛋白质聚集成超分子寡聚体，称为“炎症小体”，主要是通过它们属于死亡结构域超家族的结构域之间的同型相互作用。尽管人们对这些螺旋分子机制的形成知之甚少，但其组装动力学与每个域结构之间的详细相关性仍未得到很好的理解。使用由衔接子分子ASC的PYD域形成的细丝作为测试系统，我们构建了一个新的多尺度仿真框架来研究炎症小体组装的动力学。我们发现，灯丝组装是一个多步骤但高度协作的过程。此外，ASCPYD细丝中的域亚基之间存在三种类型的结合界面。多尺度模拟结果表明，结构域组装的动力学植根于主要蛋白质序列，该序列通过三个结合界面定义了分子识别的能量学。在介导装配的动力学和热力学方面，界面I在其他方面起着比其他两个角色更多的调节作用。最后，我们计算框架的效率使我们能够系统地设计突变体，并预测其对灯丝组装的影响。总而言之，就我们所知，这是第一个模拟炎性体装配的时空过程的模拟方法。