Most biomolecular interactions are typically thought to increase the (local) rigidity of a complex, for example, in drug‐target binding. However, detailed analysis of specific biomolecular complexes can reveal a more subtle interplay between binding and rigidity. Here, we focussed on the human leucocyte antigen (HLA), which plays a crucial role in the adaptive immune system by presenting peptides for recognition by the αβ T‐cell receptor (TCR). The role that the peptide plays in tuning HLA flexibility during TCR recognition is potentially crucial in determining the functional outcome of an immune response, with obvious relevance to the growing list of immunotherapies that target the T‐cell compartment. We have applied high‐pressure/temperature perturbation experiments, combined with molecular dynamics simulations, to explore the drivers that affect molecular flexibility for a series of different peptide–HLA complexes. We find that different peptide sequences affect peptide–HLA flexibility in different ways, with the peptide cargo tuning a network of correlated motions throughout the pHLA complex, including in areas remote from the peptide‐binding interface, in a manner that could influence T‐cell antigen discrimination.

中文翻译：

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肽货物调节人类白细胞抗原中相关运动的网络。

大多数生物分子相互作用通常被认为会增加复合物的（局部）刚性，例如，在药物-靶点结合中。然而，对特定生物分子复合物的详细分析可以揭示结合和刚性之间更微妙的相互作用。在这里，我们专注于人类白细胞抗原 (HLA)，它通过呈递供 αβ T 细胞受体 (TCR) 识别的肽在适应性免疫系统中发挥关键作用。该肽在 TCR 识别过程中在调节 HLA 灵活性方面所起的作用对于确定免疫反应的功能结果可能至关重要，这与越来越多的针对 T 细胞区室的免疫疗法明显相关。我们应用了高压/温度扰动实验，结合分子动力学模拟，探索影响一系列不同肽-HLA 复合物分子灵活性的驱动因素。我们发现不同的肽序列以不同的方式影响肽-HLA 的灵活性，肽货物以可能影响 T 细胞的方式调整整个 pHLA 复合物的相关运动网络，包括远离肽结合界面的区域抗原鉴别。