Zhu Ying, Huang Changxin, Su Meng, Ge Zuanmin, Gao Lanlan, Shi Yanfei, Wang Xuechun, Chen Jianfeng
Department of Oncology, First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China.
Department of Oncology, Affiliated Hospital of Hangzhou Normal University, Hangzhou, China.
Ann Transl Med. 2021 Mar;9(6):495. doi: 10.21037/atm-21-835.
The present study aimed to explore residues' properties interacting with HLA-A*02-restricted peptides on T-cell receptors (TCRs) and their effects on bond types of interaction and binding free energy.
We searched the crystal structures of HLA-A*02-restricted peptide-TCR complexes from the Protein Data Bank (PDB) database and subsequently collected relevant parameters. We then employed Schrodinger to analyze the bond types of interaction and Gromacs 2019 to evaluate the TCR-antigen peptide complex's molecular dynamics simulation. Finally, we compared the changes of bond types of interaction and binding free energy before and after residue substitution to ensure consistency of the conditions before and after residue substitution.
The main sites on the antigen peptides that formed the intermolecular interaction [hydrogen bond (HB) and pi stack] with TCRs were P4, P8, P2, and P6. The hydrophobicity of the amino acids inside or outside the disulfide bond of TCRs may be related to the intermolecular interaction and binding free energy between TCRs and peptides. Residues located outside the disulfide bond of TCR α or β chains and forming pi stack force played favorable roles in the complex intermolecular interaction and binding free energy. The residues of the TCR α or β chains that interacted with peptides were replaced by alanine (Ala) or glycine (Gly), and their intermolecular binding free energy of the complex had been improved. However, it had nothing to do with the formation of HB.
The findings of this study suggest that the hydrophobic nature of the amino acids inside or outside the disulfide bonds on the TCR may be associated with the intermolecular interaction and binding between the TCR and polypeptide. The residues located outside the TCR α or β single-chain disulfide bond and forming the pi-stack force showed a beneficial effect on the intermolecular interaction and binding of the complex. In addition, the part of the residues on the TCR α or β single chain that produced bond types of interaction with the polypeptide after being replaced by Ala or Gly, the intermolecular binding free energy of the complex was increased, regardless of whether HB was formed.
本研究旨在探索与T细胞受体（TCR）上HLA - A*02限制性肽相互作用的残基特性及其对相互作用键类型和结合自由能的影响。
我们从蛋白质数据库（PDB）中搜索HLA - A*02限制性肽 - TCR复合物的晶体结构，随后收集相关参数。然后我们使用薛定谔软件分析相互作用的键类型，并使用Gromacs 2019评估TCR - 抗原肽复合物的分子动力学模拟。最后，我们比较残基替换前后相互作用键类型和结合自由能的变化，以确保残基替换前后条件的一致性。
抗原肽上与TCR形成分子间相互作用[氢键（HB）和π堆积]的主要位点是P4、P8、P2和P6。TCR二硫键内外氨基酸的疏水性可能与TCR和肽之间的分子间相互作用及结合自由能有关。位于TCRα或β链二硫键外并形成π堆积力的残基在复合物分子间相互作用和结合自由能方面发挥了有利作用。将与肽相互作用的TCRα或β链残基替换为丙氨酸（Ala）或甘氨酸（Gly）后，复合物的分子间结合自由能得到了提高。然而，这与HB的形成无关。
本研究结果表明TCR上二硫键内外氨基酸的疏水性可能与TCR和多肽之间的分子间相互作用及结合有关。位于TCRα或β单链二硫键外并形成π堆积力的残基对复合物的分子间相互作用和结合显示出有益作用。此外，TCRα或β单链上被Ala或Gly替换后与多肽产生相互作用键类型的部分残基，无论是否形成HB，复合物的分子间结合自由能都会增加。
