Structure-based selection of human metabolite binding P4 pocket of DRB1*15:01 and DRB1*15:03, with implications for multiple sclerosis.

Binding of small molecules in the human leukocyte antigen (HLA) peptide-binding groove may result in conformational changes of bound peptide and an altered immune response, but previous studies have not considered a potential role for endogenous metabolites. We performed virtual screening of the complete Human Metabolite Database (HMDB) for docking to the multiple sclerosis (MS) susceptible DRB115:01 allele and compared the results to the closely related yet non-susceptible DRB115:03 allele; and assessed the potential impact on binding of human myelin basic peptide (MBP). We observed higher energy scores for metabolite binding to DRB115:01 than DRB115:03. Structural comparison of docked metabolites with DRB115:01 and DRB115:03 complexed with MBP revealed that Phenylalanine allows binding of metabolites in the P4 pocket of DRB115:01 but Valine abrogates metabolite binding in the P1 pocket. We observed differences in the energy scores for binding of metabolites in the P4 pockets of DRB115:01 vs. DRB115:03 suggesting stronger binding to DRB115:01. Our study confirmed that specific, disease-associated human metabolites bind effectively with the most polymorphic P4 pocket of DRB1*15:01, the primary MS susceptible allele in most populations. Our results suggest that endogenous human metabolites bound in specific pockets of HLA may be immunomodulatory and implicated in autoimmune disease.