CD1 molecules present lipid antigens for recognition by T-cell receptors (TCRs). Although a reasonably detailed picture of the CD1-lipid-TCR interaction exists, the initial steps regarding lipid loading onto and exchange between CD1 proteins remain elusive. The hydrophobic nature of lipids and the fact that CD1 molecules are unable to extract lipids from membranes raise the need for the assistance of helper proteins in lipid trafficking. However, the experimental study of this traffic in the endosomal compartments at which it occurs is so challenging that computational studies can help provide mechanistic insight into the associated processes. Here we present a multifaceted computational approach to obtain dynamic structural data on the human CD1d isotype. Conformational dynamics analysis shows an intrinsic flexibility associated with the protein architecture. Electrostatic properties together with molecular dynamics results for CD1d complexes with several lipids and helper proteins unravel the high dynamic plasticity of the antigen-binding site that is crucially favoured by acidic pH and the presence of helper proteins.

CD1 分子呈递脂质抗原，供 T 细胞受体 (TCR) 识别。尽管存在 CD1-脂质-TCR 相互作用的相当详细的图片，但有关 CD1 蛋白上的脂质加载和之间交换的初始步骤仍然难以捉摸。脂质的疏水性以及 CD1 分子无法从膜中提取脂质的事实提出了在脂质运输中需要辅助蛋白的协助。然而，对其发生的内体区室中的这种交通的实验研究非常具有挑战性，以至于计算研究可以帮助提供对相关过程的机械见解。在这里，我们提出了一种多方面的计算方法来获取人类 CD1d 同种型的动态结构数据。构象动力学分析显示了与蛋白质结构相关的内在灵活性。 CD1d 与多种脂质和辅助蛋白复合物的静电特性以及分子动力学结果揭示了抗原结合位点的高动态可塑性，而酸性 pH 和辅助蛋白的存在对抗原结合位点至关重要。