Unsupervised and supervised AI on molecular dynamics simulations reveals complex characteristics of HLA-A2-peptide...

Immunologic recognition of peptide antigens bound to class I major histocompatibility complex (MHC) molecules is essential to both novel immunotherapeutic development and human health at large. Current methods for predicting antigen peptide immunogenicity rely primarily on simple sequence representations, which allow for some understanding of immunogenic features but provide inadequate consideration of the full scale of molecular mechanisms tied to peptide recognition. We here characterize contributions that unsupervised and supervised artificial intelligence (AI) methods can make toward understanding and predicting MHC(HLA-A2)-peptide complex immunogenicity when applied to large ensembles of molecular dynamics simulations. We first show that an unsupervised AI method allows us to identify subtle features that drive immunogenicity differences between a cancer neoantigen and its wild-type peptide counterpart. Next, we demonstrate that a supervised AI method for class I MHC(HLA-A2)-peptide complex classification significantly outperforms a sequence model on small datasets corrected for trivial sequence correlations. Furthermore, we show that both unsupervised and supervised approaches reveal determinants of immunogenicity based on time-dependent molecular fluctuations and anchor position dynamics outside the MHC binding groove. We discuss implications of these structural and dynamic immunogenicity correlates for the induction of T cell responses and therapeutic T cell receptor design.