Usefulness of Docking and Molecular Dynamics in Selecting Tumor Neoantigens to Design Personalized Cancer Vaccines: A Proof of Concept

Personalized cancer vaccines based on neoantigens are a new and promising treatment for cancer; however, there are still multiple unresolved challenges to using this type of immunotherapy. Among these, the effective identification of immunogenic neoantigens stands out, since the in silico tools used generate a significant portion of false positives. Inclusion of molecular simulation techniques can refine the results these tools produce. In this work, we explored docking and molecular dynamics to study the association between the stability of peptide–HLA complexes and their immunogenicity, using as a proof of concept two HLA-A2-restricted neoantigens that were already evaluated in vitro. The results obtained were in accordance with the in vitro immunogenicity, since the immunogenic neoantigen ASTN1 remained bound at both ends to the HLA-A2 molecule. Additionally, molecular dynamic simulation suggests that position 1 of the peptide has a more relevant role in stabilizing the N-terminus than previously proposed. Likewise, the mutations may have a “delocalized” effect on the peptide–HLA interaction, which means that the mutated amino acid influences the intensity of the interactions of distant amino acids of the peptide with the HLA. These findings allow us to propose the inclusion of molecular simulation techniques to improve the identification of neoantigens for cancer vaccines.