Simulation code: spatial model from A spatio-temporal model reveals self-limiting Fc<i>ɛ</i>RI cross-linking by multivalent antigens.

Aggregation of cell surface receptor proteins by multivalent antigens is an essential early step for immune cell signalling. A number of experimental and modelling studies in the past have investigated multivalent ligand-mediated aggregation of IgE receptors (Fc<i>ɛ</i>RI) in the plasma membrane of mast cells. However, understanding of the mechanisms of Fc<i>ɛ</i>RI aggregation remains incomplete. Experimental reports indicate that Fc<i>ɛ</i>RI forms relatively small and finite-sized clusters when stimulated by a multivalent ligand. By contrast, modelling studies have shown that receptor cross-linking by a trivalent ligand may lead to the formation of large receptor superaggregates that may potentially give rise to hyperactive cellular responses. In this work, we have developed a Brownian dynamics-based spatio-temporal model to analyse Fc<i>ɛ</i>RI aggregation by a trivalent antigen. Unlike the existing models, which implemented non-spatial simulation approaches, our model explicitly accounts for the coarse-grained site-specific features of the multivalent species (molecules and complexes). The model incorporates membrane diffusion, steric collisions and sub-nanometre-scale site-specific interaction of the time-evolving species of arbitrary structures. Using the model, we investigated temporal evolution of the species and their diffusivities. Consistent with a recent experimental report, our model predicted sharp decay in species mobility in the plasma membrane in response receptor cross-linking by a multivalent antigen. We show that, due to such decay in the species mobility, post-stimulation receptor aggregation may become self-limiting. Our analysis reveals a potential regulatory mechanism suppressing hyperactivation of immune cells in response to multivalent antigens.多价抗原介导的细胞表面受体蛋白聚集是免疫细胞信号转导的关键早期步骤。过往已有诸多实验与建模研究，针对肥大细胞质膜上的IgE受体（FcɛRI）的多价配体介导聚集过程开展了相关探究。然而，学界对FcɛRI聚集的分子机制仍未完全阐明。实验研究表明，在多价配体刺激下，FcɛRI仅会形成尺寸有限的小型簇集结构。与之形成鲜明对比的是，建模研究显示，三价配体介导的受体交联可能会形成大型受体超聚集体，进而可能引发过度活跃的细胞应答。本研究构建了一种基于布朗动力学（Brownian dynamics）的时空模型，用于分析三价抗原介导的FcɛRI聚集过程。与过往采用非空间模拟方法的现有模型不同，本模型显式考虑了多价物种（包括分子与复合物）的粗粒度位点特异性特征。该模型涵盖了膜扩散、空间位阻碰撞以及任意结构的时变物种的亚纳米级位点特异性相互作用。借助该模型，我们探究了各类物种的时间演化过程及其扩散特性。研究结果与近期一项实验报道相符：当多价抗原介导受体交联时，质膜上的物种迁移率会出现显著下降。我们发现，正是由于这种迁移率的下降，刺激后的受体聚集过程会呈现自限性特征。本研究的分析结果揭示了一种潜在的调控机制，可抑制免疫细胞在多价抗原刺激下发生过度活化。