Huang Changxin, Chen Jianfeng, Ding Fei, Yang Lili, Zhang Siyu, Wang Xuechun, Shi Yanfei, Zhu Ying
Department of Oncology, Affiliated Hospital of Hangzhou Normal University, Hangzhou, China.
Department of Proctology, Affiliated Hospital of Hangzhou Normal University, Hangzhou, China.
Ann Transl Med. 2021 Apr;9(8):673. doi: 10.21037/atm-21-630.
Major histocompatibility complex class I (MHC-I) plays an important role in cell immune response, and stable interaction between polypeptides and MHC-I ensures efficient presentation of polypeptide-MHC-I (pMHC-I) molecular complexes to T cells. The aim of this study was to explore ways to improve the affinity and stability of the p-Human Leukocyte Antigen (HLA)-A*2402 complex.
The peptide sequences of the restricted antigen peptides for HLA-A2402 and the results of the competitive binding test were retrieved from the literature. The affinity values were predicted using NetMHCpan v4.1 server, and the stability values were predicted using the NetMHCstab v1.0 server. Auto Vina was used to dock peptides to HLA-A2402 protein in a flexible docking manner, while Flexpepdock was employed to optimize the docking morphology. Maestro was used to analyze the intermolecular forces and the binding affinity of the complex, while MM-GBSA was used to calculate the binding free energy values.
The intermolecular interactions that maintained the affinity and stability of peptide-HLA-A2402 complex relied mainly on HB, followed by pi stack. The binding affinity values of molecular docking were associated with the predicted values of affinity and stability, the binding affinity and the binding free energy, as well as the intermolecular force pi-stack. The pi stack had a significant negative correlation with binding affinity and binding free energy. The replacement of the residues of the polypeptides that did not form pi-stack interactions with HLA-A2402 improved the affinity and/or stability compared to before replacement.
The generation and increase in the number of pi-stacks between peptides and HLA-A2402 molecules may help improve the affinity and stability of p-HLA-A2402 complexes. The prediction of intermolecular forces and binding affinity of peptide-HLA by means of molecular docking is a supplement to the current commonly used prediction databases.
主要组织相容性复合体I类（MHC-I）在细胞免疫反应中起重要作用，多肽与MHC-I之间的稳定相互作用确保了多肽-MHC-I（pMHC-I）分子复合物向T细胞的有效呈递。本研究的目的是探索提高p-人类白细胞抗原（HLA）-A*2402复合物亲和力和稳定性的方法。
从文献中检索HLA-A2402限制性抗原肽的肽序列和竞争性结合试验结果。使用NetMHCpan v4.1服务器预测亲和力值，使用NetMHCstab v1.0服务器预测稳定性值。Auto Vina用于以柔性对接方式将肽与HLA-A2402蛋白对接，同时使用Flexpepdock优化对接形态。Maestro用于分析复合物的分子间作用力和结合亲和力，而MM-GBSA用于计算结合自由能值。
维持肽-HLA-A2402复合物亲和力和稳定性的分子间相互作用主要依赖于氢键（HB），其次是π堆积。分子对接的结合亲和力值与亲和力和稳定性的预测值、结合亲和力和结合自由能以及分子间力π堆积相关。π堆积与结合亲和力和结合自由能呈显著负相关。与替换前相比，替换与HLA-A2402不形成π堆积相互作用的多肽残基可提高亲和力和/或稳定性。
肽与HLA-A2402分子之间π堆积的产生和数量增加可能有助于提高p-HLA-A2402复合物的亲和力和稳定性。通过分子对接预测肽-HLA的分子间作用力和结合亲和力是对当前常用预测数据库的补充。
