Molecular Insights into Tumor Immunogenicity
2025
Irini Doytchinova | Stanislav Sotirov | Ivan Dimitrov
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&mdash:38 T-cell epitopes and 144 non-epitopes&mdash:were compiled and analyzed using sequence logo models and molecular dynamics (MD) simulations of TCR&ndash:peptide&ndash:HLA complexes. A comparative logo analysis revealed strong amino acid preferences at central positions (p4&ndash:p8) in T-cell epitopes and absences in non-epitopes. A representative epitope&ndash: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 &pi: interactions across the residues at positions p4&ndash:p8. In contrast, the non-epitope engaged TCR at only two positions. These findings highlight the critical role of the peptide&rsquo:s central region in TCR engagement and provide structural insights useful for neoantigen prediction, vaccine design, and TCR-based immunotherapies.
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