Computational prediction of the peptides presented on major histocompatibility complex (MHC) class I proteins is an important tool for studying T cell immunity. The data available to develop such predictors have expanded with the use of mass spectrometry to identify naturally presented MHC ligands. In addition to elucidating binding motifs, the identified ligands also reflect the antigen processing steps that occur prior to MHC binding. Here, we developed an integrated predictor of MHC class I presentation that combines new models for MHC class I binding and antigen processing. Considering only peptides first predicted by the binding model to bind strongly to MHC, the antigen processing model is trained to discriminate published mass spectrometry-identified MHC class I ligands from unobserved peptides. The integrated model outperformed the two individual components as well as NetMHCpan 4.0 and MixMHCpred 2.0.2 on held-out mass spectrometry experiments. Our predictors are implemented in the open source MHCflurry package, version 2.0 (github.com/openvax/mhcflurry).
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