Doytchinova Irini, Sotirov Stanislav, Dimitrov Ivan
Drug Design and Bioinformatics Lab, Faculty of Pharmacy, Medical University of Sofia, Dunav St. 2, 1000 Sofia, Bulgaria.
Curr Issues Mol Biol. 2025 Aug 11;47(8):641. doi: 10.3390/cimb47080641.
Tumor immunogenicity depends on the ability of peptides to form stable and specific interactions with both HLA molecules and T-cell receptors (TCRs). While HLA binding is essential, not all HLA-binding peptides elicit T-cell responses. This study investigates the molecular features distinguishing immunogenic T-cell epitopes from non-immunogenic HLA binders. Two datasets of nonamer peptides-38 T-cell epitopes and 144 non-epitopes-were compiled and analyzed using sequence logo models and molecular dynamics (MD) simulations of TCR-peptide-HLA complexes. A comparative logo analysis revealed strong amino acid preferences at central positions (p4-p8) in T-cell epitopes and absences in non-epitopes. A representative epitope-non-epitope pair was selected for structural modeling and 100 ns MD simulations. The T-cell epitope formed a more stable complex with the TCR and exhibited greater flexibility, supporting an induced-fit recognition mechanism. It also established a broader and longer-lasting network of hydrogen bonds and π interactions across the residues at positions p4-p8. In contrast, the non-epitope engaged TCR at only two positions. These findings highlight the critical role of the peptide's central region in TCR engagement and provide structural insights useful for neoantigen prediction, vaccine design, and TCR-based immunotherapies.
肿瘤免疫原性取决于肽段与人类白细胞抗原（HLA）分子和T细胞受体（TCR）形成稳定且特异性相互作用的能力。虽然HLA结合至关重要，但并非所有与HLA结合的肽段都会引发T细胞反应。本研究调查了区分免疫原性T细胞表位与非免疫原性HLA结合肽的分子特征。利用序列标识模型和TCR-肽段-HLA复合物的分子动力学（MD）模拟，编制并分析了九聚体肽段的两个数据集——38个T细胞表位和144个非表位。比较性的标识分析揭示了T细胞表位中心位置（p4-p8）存在强烈的氨基酸偏好，而非表位则没有。选择了一对具有代表性的表位-非表位进行结构建模和100纳秒的MD模拟。T细胞表位与TCR形成了更稳定的复合物，并表现出更大的灵活性，支持诱导契合识别机制。它还在p4-p8位置的残基间建立了更广泛、更持久的氢键和π相互作用网络。相比之下，非表位仅在两个位置与TCR结合。这些发现突出了肽段中心区域在TCR结合中的关键作用，并为新抗原预测、疫苗设计和基于TCR的免疫疗法提供了有用的结构见解。
