The stimulator of interferon genes (STING) protein is a cornerstone of the human immune response. Its activation by cGAMP in the presence of cytosolic DNA stimulates the production of type I interferons and inflammatory cytokines. In the human population, several STING variants exist and exhibit dramatic differences in their activity, impacting the efficiency of the host defense against infections. Understanding the molecular mechanisms of these variants opens perspectives for personalized medicine treatments against diseases such as viral infections, cancers, or autoinflammatory diseases. Through microsecond-scale molecular modeling simulations, contact analyses, and machine learning techniques, we reveal the dynamic behavior of four STING variants (wild type, G230A, R293Q, and G230A/R293Q) and rationalize the variability of efficiency observed experimentally. Our results show that the decrease in STING activity is linked to a stiffening of key structural elements of the binding cavity together with changes in the interaction patterns within the protein.

中文翻译：

---

我们有多脆弱：干扰素基因刺激物 (STING) 变异体对病原体识别和免疫反应效率的影响

干扰素基因刺激物 (STING) 蛋白是人类免疫反应的基石。在细胞溶质 DNA 存在的情况下，cGAMP 对其的激活会刺激 I 型干扰素和炎性细胞因子的产生。在人群中，存在几种 STING 变体，它们的活动表现出巨大差异，影响宿主防御感染的效率。了解这些变体的分子机制为针对病毒感染、癌症或自身炎症性疾病等疾病的个性化药物治疗开辟了前景。通过微秒级分子建模模拟、接触分析和机器学习技术，我们揭示了四种 STING 变体（野生型、G230A、R293Q、和 G230A/R293Q）并合理化实验观察到的效率变异性。我们的结果表明，STING 活性的降低与结合腔的关键结构元素的硬化以及蛋白质内相互作用模式的变化有关。