Accelerating Molecular Dynamics with Hydrogen Mass Repartitioning to Prioritize Immunogenic Neoantigens for Cancer Vaccines through Peptide–HLA Binding Free-Energy Calculations
Year: 2026
Type: preprint
Abstract: Personalized neoantigen-based vaccines have progressed from concept to clinical evidence for some of the most aggressive human tumors, yet a key challenge remains: determining which candidates should be prioritized for vaccine inclusion. Public neoantigens, shared across tumor subtypes and patient populations, offer potential as off-the-shelf candidates for broad-spectrum immunotherapy. Candidate selection relies on in silico pipelines that estimate binding; however, binding affinity alone is an imperfect marker of immunogenicity. Molecular dynamics (MD) combined with endpoint free-energy methods estimates binding free energy directly from simulated trajectories, and hydrogen mass repartitioning (HMR) mitigates the computational cost of hydrogen-involving bond vibrations. This study assessed whether HMR-accelerated MD can prioritize immunogenic neoantigens through peptide–HLA binding free-energy calculations and quantified the trade-off between accuracy and computational cost. Ten immunogenic public neoantigens (seven paired with their wild-type counterparts and three frameshift neoantigens analyzed as unpaired references) were modeled in complex with their HLA-I alleles, built de novo using AlphaFold3 and propagated with a 4-fs HMR time step. Mean binding free energy was computed across ten replicas per complex, and each SNV pair was scored concordant with experimental data when the neoantigen formed a more favorable complex than its wild type. Free energies were recomputed at 100–500 ns to identify the shortest trajectory preserving reliable ranking. Free-energy calculations reproduced experimental concordance for six of seven SNV pairs and were inconclusive for TP53 R8H; frameshift neoantigens yielded comparable values. Most complexes retained both peptide termini anchored to the HLA groove throughout, and RMSD and RMSF metrics agreed with one another and with the free-energy rankings. The PIK3CA E545K (E11K) pair showed the most distinctive signature: the peptides engaged the groove almost identically over P1–P8, with the entire difference confined to the C-terminal pocket, where loss of the wild-type’s anchor also disrupted its backbone anchor. This pair showed the largest free-energy separation in the panel, and restricting analysis to bound frames confirmed a substantial electrostatic and van der Waals advantage favoring the neoantigen. These findings support HMR-accelerated binding free-energy MD as a practical refinement step for neoantigen prioritization and its application to assessing public neoantigens for cancer vaccine design.
Institution: Universidad Nacional de Colombia
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Award: G2696953474
OpenAlex ID: W7222873497