Institute of Biosimulation and Bioinformatics, Center for Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria.
BMC Immunol. 2022 Jul 29;23(Suppl 1):36. doi: 10.1186/s12865-022-00510-7.
Major histocompatibility complexes (MHCs) play a crucial role in the cell-mediated adaptive immune response as they present antigenic peptides (p) which are recognized by host T cells through a complex formation of the T cell receptor (TCR) with pMHC. In the present study, we report on changes in conformational flexibility within a pMHC molecule upon TCR binding by looking at molecular dynamics (MD) simulations of the free and the TCR-bound pMHC-I protein of the LC13-HLA-B*44:05-pEEYLQAFTY complex.
We performed long-term MD simulations with a total simulation time of 8 µs, employing 10 independent 400 ns replicas for the free and the TCR-bound pMHC system. Upon TCR ligation, we observed a reduced dynamic flexibility in the central residues of the peptide and the MHC α1-helix, altered occurrences of hydrogen bonds between the peptide and the MHC, a reduced conformational entropy of the peptide-binding groove, as well as a decreased solvent accessible surface area.
In summary, our results from 8 µs MD simulations indicate a restricted conformational space of the MHC peptide-binding groove upon TCR ligation and suggest a minimum simulation time of approximately 100 ns for biomolecules of comparable complexity to draw meaningful conclusions. Given the relatively long total simulation time, our results contribute to a more detailed view on conformational flexibility properties of the investigated free and TCR-bound pMHC-I system.
主要组织相容性复合体（MHCs）在细胞介导的适应性免疫反应中起着至关重要的作用，因为它们呈现抗原肽（p），宿主 T 细胞通过 TCR 与 pMHC 的复杂形成来识别这些抗原肽。在本研究中，我们报告了 TCR 结合后 pMHC 分子构象灵活性的变化，方法是观察游离和 TCR 结合的 LC13-HLA-B*44:05-pEEYLQAFTY 复合物的 pMHC-I 蛋白的分子动力学（MD）模拟。
我们进行了总模拟时间为 8µs 的长期 MD 模拟，对于游离和 TCR 结合的 pMHC 系统，使用了 10 个独立的 400ns 副本。在 TCR 连接后，我们观察到肽和 MHC α1-螺旋的中心残基的动态灵活性降低，肽和 MHC 之间氢键的出现改变，肽结合槽的构象熵降低，以及溶剂可及表面积减少。
总之，我们来自 8µs MD 模拟的结果表明，TCR 连接后 MHC 肽结合槽的构象空间受到限制，并建议对于具有类似复杂性的生物分子，模拟时间约为 100ns，以得出有意义的结论。考虑到相对较长的总模拟时间，我们的结果有助于更详细地了解所研究的游离和 TCR 结合的 pMHC-I 系统的构象灵活性特性。
