Activation of T cells triggers the expression of regulatory molecules like the programmed cell death 1 (PD1) protein. The association of PD1 with the natural ligands PDL1 and PDL2 induces an inhibitory signal that prevents T cells from proliferating and exerting effector functions. However, little is known about how the binding of the ligands induce the PD1 inhibitory signal over T cells effector functions. Here, we explore the dynamics of PD1 free, and in complex with different PDL1 variants as well as the therapeutic antibodies nivolumab and pembrolizumab in order to assess the conformational changes in PD1 related to the signaling process. Our simulations suggest a pre‐conformational selection mechanism for the binding of the different PDL1 variants, while an induced‐fit model fits better for the molecular recognition process of the therapeutic antibodies. A deep analysis of the changes on PD1 movement upon the binding to different ligands revealed that as larger is the difference in the conformation adopted by loop C′D with respect to the complex with PDL1 is higher the ligand ability to reduce the PD1 inhibitory signaling. This behavior suggests that targeting specific conformations of this loop can be useful for designing therapies able to recover T cells effector functions.

中文翻译：

---

探索具有不同配体的复合物中PD1的构象动力学：设计新型PD1信号传导阻滞剂可以学到什么？

T细胞的激活触发调节分子的表达，例如程序性细胞死亡1（PD1）蛋白。PD1与天然配体PDL1和PDL2的缔合会诱导抑制信号，阻止T细胞增殖并发挥效应子功能。然而，关于配体的结合如何在T细胞效应子功能上诱导PD1抑制信号知之甚少。在这里，我们探讨了无PD1的动力学，并与不同的PDL1变异体以及治疗性抗体nivolumab和pembrolizumab结合使用，以评估与信号转导过程相关的PD1的构象变化。我们的模拟为不同PDL1变体的结合提出了一种构象前的选择机制，诱导拟合模型更适合治疗性抗体的分子识别过程。对与不同配体结合后PD1运动变化的深入分析表明，环C'D相对于具有PDL1的复合物所采用的构象差异越大，配体减少PD1抑制信号的能力越高。此行为表明，靶向此环的特定构象可用于设计能够恢复T细胞效应子功能的疗法。