BPS2026 – Molecular dynamics simulations under load of three distinct T cell receptors recognizing the same truncal tumor TP53 neoantigen reveal differential stability of their TCR-pHLA complexes

The TP53 is one of the most important oncogenes as it encodes the tumor suppressor protein p53, which is mutated in about 40% to 50% of cancers. Mutant p53 often drives tumor development associated with poor therapeutic response. A major hotspot truncal mutation of TP53 is R175H, located in the DNA-binding domain of p53. T cell receptors (TCRs) 12-6, 38-10, and 6-11, isolated from tumor-infiltrating lymphocytes of epithelial cancer patients, can recognize a neoepitope spanning residues 168–176 of the mutant p53R175H presented by HLA-A ∗ 02:01 (TCR-pHLA). TCRs 12-6 and 38-10 both bind toward the C terminal end of the peptide, focusing on P8-His, which allows them to discriminate the mutant from the wild-type peptide. In contrast, TCR 6-11 does not directly contact P8-His, and it is believed that the reduced desolvation cost of the R175H mutation improves recognition. However, those observations are based on static crystal structures, and it is unclear how the interface behaves in a dynamically fluctuating environment, especially under mechanical force applied to the complex during immune surveillance. To elucidate the differences in dynamic mechanisms of the neoantigen recognition among the three TCRs, we use all-atom molecular dynamics simulations with picoNewton level loads applied to the complexes. We found that under applied mechanical force, TCR 12-6 maintains a more stable interface compared to TCR 6-11 despite their comparable equilibrium binding affinity. TCR 38-10 that has 10-fold weaker equilibrium binding affinity than the other two, showed greater stability under load compared to TCR 6-11. Notably, these results indicate that the three TCRs may operate under different mechanical conditions in vivo.