Abstract
The accurate prediction of peptide-major histocompatibility complex (MHC) class I binding probabilities is a critical endeavor in immunoinformatics, with broad implications for vaccine development and immunotherapies. While recent deep neural network based approaches have showcased promise in peptide-MHC (pMHC) prediction, they have two shortcomings: (i) they rely on hand-crafted pseudo-sequence extraction, (ii) they do not generalize well to different datasets, which limits the practicality of these approaches. While existing methods rely on a 34 amino acid pseudo-sequence, our findings uncover the involvement of 147 positions in direct interactions between MHC and peptide. We further show that neural architectures can learn the intricacies of pMHC binding using even full sequences. To this end, we present PerceiverpMHC that is able to learn accurate representations on full-sequences by leveraging efficient transformer based architectures. Additionally, we propose IMGT/RobustpMHC that harnesses the potential of unlabeled data in improving the robustness of pMHC binding predictions through a self-supervised learning strategy. We extensively evaluate RobustpMHC on eight different datasets and showcase an overall improvement of over 6% in binding prediction accuracy compared to state-of-the-art approaches. We compile CrystalIMGT, a crystallography-verified dataset presenting a challenge to existing approaches due to significantly different pMHC distributions. Finally, to mitigate this distribution gap, we further develop a transfer learning pipeline.