Trans-Allelic Model for Prediction of Peptide:MHC-II Interactions

Major histocompatibility complex class two {(MHC-II)} molecules are trans-membrane proteins and key components of the cellular immune system. Upon recognition of foreign peptides expressed on the MHC-II binding groove, {{red} CD4⁺ T cells mount an immune} in mounting response against invading pathogens. Therefore, mechanistic identification and knowledge of physico-chemical features that govern interactions between peptides and MHC-II molecules is useful for the design of effective epitope-based vaccines, as well as for understanding of immune responses. In this paper, we present a comprehensive trans-allelic prediction model, a generalized version of our previous biophysical model, that can predict peptide interactions for all three human MHC-II loci (HLA-DR, HLA-DP and HLA-DQ), using both peptide sequence data and structural information of MHC-II molecules. The advantage of this approach over other machine learning models is that it offers a simple and plausible physical explanation for peptide-MHC-II interactions. We train the model using a benchmark experimental dataset, and measure its predictive performance using novel data. Despite its relative simplicity, we find that the model has comparable performance to the state-of-the-art method, {{red}the NetMHCIIpan method}. Focusing on the physical {{red} basis} of peptide-MHC binding, we find support for previous theoretical predictions about the contributions of certain binding pockets to the binding energy. Additionally, we find that binding pocket $P5$ of HLA-DP, which was not previously considered as a primary anchor, does make strong contribution to the binding energy. Together, the results indicate that our model can serve as a useful complement to alternative approaches to predicting peptide-MHC interactions.