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首页> 外文期刊>Journal of Biomolecular Structure and Dynamics >Exploring the different states of wild-type T-cell receptor and mutant conformational changes towards understanding the antigen recognition
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Exploring the different states of wild-type T-cell receptor and mutant conformational changes towards understanding the antigen recognition

机译：探索野生型T细胞受体和突变体构象变化的不同状态，以了解抗原识别

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摘要

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 wildtype 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 (6 mu s). 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 CDR alpha 3 and CDR beta 3 loops showed significant structural changes. Interestingly, the TCR beta chain loops showed the least changes, which is reliable with recent implications that beta 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 CDR alpha 3 loop and can allow enhanced binding affinity of the peptide antigen. Additionally, we show that CDR alpha 3 loop and peptide contacts are an adaptive feature of affinity enhanced mutant TCR.
机译：T细胞受体（TCR）识别主要组织相容性复合体（MHC）在靶细胞上呈现的蛋白水解肽片段是适应性免疫系统中最重要的相互作用之一。为了研究TCR增强免疫原性的构象和动力学特性，已经进行了一些计算研究。在这里，我们对野生型和突变型IG4 TCR与肿瘤表位NY-ESO肽（SLLMWITQC）组成的两个综合系统进行了大规模分子动力学（MD）模拟研究，并分析了TCR在抗原结合前、抗原结合后和抗原释放后的构象变化。所有模拟都是在每1000 ns模拟时间的不同TCR状态下进行的，提供了6000 ns（6μs）持续时间的六个模拟。我们发现，与抗原结合时发生最关键的构象变化相比，互补决定区（CDR）环路的高比例变化相对较小。高变CDRα3和CDRβ3环显示出显著的结构变化。有趣的是，TCRβ链环显示出最小的变化，这是可靠的，最近暗示TCRβ结构域可能促进抗原相互作用。即使在释放状态下，突变体也比野生型表现出更高的刚性；暴露CDRα3环重组产生的诱导贴合机制，可增强肽抗原的结合亲和力。此外，我们还表明CDRα3环和肽接触是亲和增强突变体TCR的适应性特征。

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