Abstract
Hyper polymorphic major histocompatibility class I (MHC) molecules are key components for acquired immune responses. They have high specificity towards peptides presented to CD8 + T cells, resembling vaccine design and autoimmunity. However, a broader landscape over such a diverse set of evolutionary HLA molecules (in humans) and its structural variance in their crucial ectodomains or transmembrane regions remains elusive. Herein, we examined family-wide conserved HLA-A, HLA-B, and HLA-C alleles, and imputed structures over their full-length sequences. Despite high polymorphism among individual HLA molecules, the preserved amino acids remain proximal to C-terminus antigen binding sites. The HLA-A alleles with fewer evolutionary sub-branch have high affinity structures at both active (presenting peptides to T-cells) and inactive states of antigen cleft, compared to that of HLA-B and HLA-C. The cell-surface HLA molecules adopted better energy structures that are crucial for peptide binding and selectivity. HLA allelic families of HLA-A*02, HLA-B*57, and HLA-C*03 have shown well-defined novel secondary structures, compared to other variants. Particularly, the HLA-C alleles have structural deficiencies (insertions and sequence variability) within member-embedded domains, as well as lower internal contact energy compared to other class I HLAs. The neglected non-expressed alleles formed poor secondary structures, which reflect weaker potential to present peptides to T-cell receptors. Internal energies measured shall enable the quantification of the expressed or partially expressed HLA molecules over the cell surface. Comprehending such common structural assemblies of HLAs can guide the peptide-based vaccine development for patients with compromised immunity relating to antigen presentation.