The major histocompatibility complex class-I (MHC-I) peptide-loading complex (PLC) is a cornerstone of the human adaptive immune system, being responsible for processing antigens that allow killer T cells to distinguish between healthy and compromised cells. Based on a recent low-resolution cryo-electron microscopy (cryo-EM) structure of this large membrane-bound protein complex, we report an atomistic model of the PLC and study its conformational dynamics on the multimicrosecond time scale using all-atom molecular dynamics (MD) simulations in an explicit lipid bilayer and water environment (1.6 million atoms in total). The PLC has a layered structure, with two editing modules forming a flexible protein belt surrounding a stable, catalytically active core. Tapasin plays a central role in the PLC, stabilizing the MHC-I binding groove in a conformation reminiscent of antigen-loaded MHC-I. The MHC-I–linked glycan steers a tapasin loop involved in peptide editing toward the binding groove. Tapasin conformational dynamics are also affected by calreticulin through a conformational selection mechanism that facilitates MHC-I recruitment into the complex.

主要组织相容性复合物 I 类 (MHC-I) 肽负载复合物 (PLC) 是人类适应性免疫系统的基石，负责处理抗原，使杀伤性 T 细胞能够区分健康细胞和受损细胞。基于这种大型膜结合蛋白复合物的最新低分辨率冷冻电子显微镜（cryo-EM）结构，我们报告了 PLC 的原子模型，并使用全原子分子动力学研究了其在多微秒时间尺度上的构象动力学(MD) 显式脂质双层和水环境中的模拟（总共 160 万个原子）。 PLC具有分层结构，两个编辑模块形成围绕稳定的催化活性核心的柔性蛋白质带。 Tapasin 在 PLC 中发挥核心作用，稳定 MHC-I 结合沟，使其构象与负载抗原的 MHC-I 相似。 MHC-I 连接的聚糖将参与肽编辑的 Tapasin 环引导至结合槽。 Tapasin 构象动力学也通过构象选择机制受到钙网蛋白的影响，该机制有利于 MHC-I 募集到复合物中。