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Abstract
The selection of peptides presented by MHC molecules is crucial for antigen discovery. Previously, several predictors have shown impressive performance on binding affinity. However, the decisive MHC residues and their relation to the selection of binding peptides are still unrevealed. Here, we connected HLA alleles with binding motifs via our deep learning-based framework, MHCfovea. MHCfovea expanded the knowledge of MHC-I-binding motifs from 150 to 13,008 alleles. After clustering N-terminal and C-terminal sub-motifs on both observed and unobserved alleles, MHCfovea calculated the hyper-motifs and the corresponding allele signatures on the important positions to disclose the relation between binding motifs and MHC-I sequences. MHCfovea delivered 32 pairs of hyper-motifs and allele signatures (HLA-A: 13, HLA-B: 12, and HLA-C: 7). The paired hyper-motifs and allele signatures disclosed the critical polymorphic residues that determine the binding preference, which are believed to be valuable for antigen discovery and vaccine design when allele specificity is concerned.
Highlights
The selection of peptides presented by MHC molecules is crucial for antigen discovery
The predictor in the prediction module is constructed of an ensemble model based on convolutional neural networks (CNN) (Supplementary Fig. 1) embedded with ScoreCAM17, a class activation mapping (CAM)-based[18] approach, to highlight the important positions of the input Major histocompatibility complex class I (MHC-I) sequences
The corresponding signatures of MHC-I sequences on the important positions were generated to reveal the relation between MHC-I sequences and their binding motifs
Summary
The selection of peptides presented by MHC molecules is crucial for antigen discovery. We connected HLA alleles with binding motifs via our deep learning-based framework, MHCfovea. After clustering N-terminal and C-terminal submotifs on both observed and unobserved alleles, MHCfovea calculated the hyper-motifs and the corresponding allele signatures on the important positions to disclose the relation between binding motifs and MHC-I sequences. The paired hyper-motifs and allele signatures disclosed the critical polymorphic residues that determine the binding preference, which are believed to be valuable for antigen discovery and vaccine design when allele specificity is concerned. It is difficult to select antigens from numerous peptides for each MHC allele via experiments. In order to facilitate the process of antigen discovery, several predictors have been developed and shown accurate performance on MHC-I–peptide binding affinity[11,12]. It is difficult to specify the key residues of each motif group from the limited number of alleles with experimental measurements
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