Deciphering the selective binding mechanisms of anaplastic lymphoma kinase-derived neuroblastoma tumor neoepitopes to human leukocyte antigen.

Neuroblastoma (NB), as a metastatic form of solid tumor, has a high fatality rate found in early childhood. The two anaplastic lymphoma kinase (ALK) neoepitopes nonamer and decamer used in cancer immunotherapy against NB cancer can selectively bind to the human leukocyte antigen (HLA-B15:01) groove with high affinities, whereas the native self-peptide is unable to interact with the HLA-B15:01. Here, we performed molecular dynamics (MD) simulations and subsequent molecular mechanics-generalized born surface area (MM-GBSA) binding free energy calculations to explore the selective binding mechanisms of nonamer and decamer to the HLA-B15:01 against the self-peptide. MD simulations revealed the significant conformational dynamics of the self-peptide in the HLA-B15:01 groove against the nonamer and decamer. Binding free energy calculations showed that the binding affinities of HLA-B15:01-neoepitope complexes were followed in the order decamer > nonamer > self-peptide. Detailed analysis of HLA-B15:01-neoepitope structural complexes showed that compared to the nonamer, the self-peptide tended to move outward to the solvent, whereas the decamer moved deep to the HLA-B15:01 groove. These different dynamic observations of the ALK neoepitopes can explain the distinct binding affinities of self-peptide, nonamer, and decamer to the HLA-B15:01. The results may be useful for the design of more selective ALK neoepitopes.