Exploring the different states of wild-type T-cell receptor and mutant conformational changes towards understanding the antigen recognition

Recognition of proteolytic peptide fragments presented by major histocompatibility complex (MHC) on target cells by T-cell receptor (TCR) is among the most important interactions in the adaptive immune system. Several computational studies have been performed to investigate conformational and dynamical properties of TCRs for enhanced immunogenicity. Here, we present the large-scale molecular dynamics (MD) simulation studies of the two comprehensive systems consisting of the wild-type and mutant IG4 TCR in complex with the tumor epitope NY-ESO peptide (SLLMWITQC) and analyzed for mapping conformational changes of TCR in the states prior to antigen binding, upon antigen binding and after the antigen was released. All of the simulations were performed with different states of TCRs for each 1000 ns of simulation time, providing six simulations for time duration of 6000 ns (6µs). We show that rather than undergoing most critical conformational changes upon antigen binding, the high proportion of complementarity-determining region (CDR) loops change by comparatively small amount. The hypervariable CDRα3 and CDRβ3 loops showed significant structural changes. Interestingly, the TCR β chain loops showed the least changes, which is reliable with recent implications that β domain of TCR may propel antigen interaction. The mutant shows higher rigidity than wild-type even in released state; expose an induced fit mechanism occurring from the re-structuring of CDRα3 loop and can allow enhanced binding affinity of the peptide antigen. Additionally, we show that CDRα3 loop and peptide contacts are an adaptive feature of affinity enhanced mutant TCR. Communicated by Ramaswamy H. Sarma The wild-type has sampled significantly larger conformational changes than the mutant even in the released state.

T细胞受体（T-cell receptor, TCR）识别靶细胞表面主要组织相容性复合体（major histocompatibility complex, MHC）呈递的蛋白水解肽段，是适应性免疫系统中最为关键的相互作用之一。已有多项计算研究针对TCR的构象与动力学特性展开探究，以优化其免疫原性。本研究报道了两套完整体系的大规模分子动力学（molecular dynamics, MD）模拟研究：两套体系分别为野生型与突变型IG4 TCR与肿瘤表位NY-ESO肽（SLLMWITQC）形成的复合物，并针对抗原结合前、抗原结合过程中以及抗原解离后三种状态下TCR的构象变化进行了映射分析。所有模拟均针对不同状态的TCR开展，单条模拟时长为1000 ns，总计完成6组模拟，总模拟时长达6000 ns（即6 µs）。研究结果显示，多数互补决定区（complementarity-determining region, CDR）环的构象改变幅度相对较小，而非在抗原结合时发生最为关键的构象变化。其中高变的CDRα3与CDRβ3环呈现出显著的结构改变。值得注意的是，TCR β链环的构象变化幅度最小，这与近期提出的"TCR β结构域可驱动抗原相互作用"的研究推论相一致。即便在抗原解离状态下，突变型TCR的刚性仍高于野生型；该突变体通过CDRα3环的重构触发诱导契合机制，可提升肽抗原的结合亲和力。此外，研究表明CDRα3环与肽段的接触位点是亲和力增强型突变TCR的适应性特征。本文由Ramaswamy H. Sarma通讯。即便在抗原解离状态下，野生型TCR所采样的构象变化幅度仍显著大于突变型TCR。