Usefulness of docking and molecular dynamics in selecting tumor neoantigens to design personalized cancer vaccines: a proof of concept.

Personalized cancer vaccines are presented as a new and promising treatment alternative for cancer, especially in those cases where effective treatments do not yet exist. However, multiple challenges remain to be resolved so that this type of immunotherapy can be used in the clinical setting. Among these, the effective identification of immunogenic peptides stands out, since the in-silico tools currently used generate a significant portion of false positives. This is where molecular simulation techniques can play an important role when it comes to refining the results produced by these tools. In the present work, we explore the use of molecular simulation techniques such as docking and molecular dynamics to study the relationship between stability of peptide-HLA complexes and their immunogenicity using two HLA-A2-restricted neoantigens that have already been evaluated in vitro. The results obtained agreed with the in vitro immunogenicity of the immunogenic neoantigen ASTN1 the only one that remains bound at both ends to the HLA-A2 molecule. Additionally, molecular dynamics indicates that position 1 of the peptide has a more important role in stabilizing the N-terminal part than previously assumed. Likewise, the results suggest that the mutations may have a "delocalized" effect on the peptide-HLA interaction, that is, they may modulate the intensity of the interactions of other amino acids in the peptide. These results highlight the suitability of this type of in silico strategy to identify peptides that form stable complexes with HLA proteins that are highly immunogenic for CD8+ T cells.