Molecular and structural determinants of adamantyl susceptibility to HLA-DRs allelic variants: an in silico approach to understand the mechanism of MLEs

Class II major histocompatibility complex (MHC II) molecules as expressed by antigen-presenting cells are heterodimeric cell-surface glycoprotein receptors that are fundamental in initiating and propagating an immune response by presenting tumor-associated antigenic peptides to CD4⁺/T_H cells. The loading efficiency of such peptides can be improved by small organic compounds (MHC Loading Enhancers—MLEs), that convert the non-receptive peptide conformation of MHC II to a peptide-receptive conformation. In a reversible reaction, these compounds open up the binding site of MHC II molecules by specific interactions with a yet undefined pocket. Here, we performed molecular docking and molecular dynamics simulation studies of adamantyl compounds on the predicted cavity around the P1 pocket of 2 allelic variants of HLA-DRs. The purpose was to investigate the suitability of adamantyl compounds as MLEs at the dimorphic β86 position. Docking studies revealed that besides numerous molecular interactions formed by the adamantyl compounds, Asnβ82, Tyrβ83, and Thrβ90 are the crucial amino acid residues that are characterized as the “sensors” of peptide loading. Molecular dynamics simulation studies exposed the dynamical structural changes that HLA-DRs adopted as a response to binding of 3-(1-adamantyl)-5-hydrazidocarbonyl-1H-pyrazole (AdCaPy). The conformations of AdCaPy complexed with the Glyβ86 HLA-DR allelic variant are well correlated with the stabilized form of peptide-loaded HLA-DRs, further confirming the role of AdCaPy as a MLE. Hydrogen bonding interaction analysis clearly demonstrated that after making suitable contacts with AdCaPy, HLA-DR changes its local conformation. However, AdCaPy complexed with HLA-DR having Valβ86 at the dimorphic position did not accommodate AdCaPy as MLE due to steric hindrance caused by the valine.