All-Atom Simulations Reveal a Key Interaction Network in the HLA-E/NKG2A/CD94 Immune Complex Fine-Tuned by the Nonameric Peptide

Natural killer (NK)
cells, an important part of the innate immune
system, can clear a wide variety of pathological challenges, including
tumor, senescent, and virally infected cells. They express various
activating and inhibitory receptors on their surface, and the balance
of interactions between them and specific ligands displayed on the
surface of target cells is critical for NK cell cytolytic function
and target cell protection. The CD94/NKG2A heterodimer is one of the
inhibitory receptors that interacts with its trimeric ligand consisting
of HLA-E, β2m, and a nonameric peptide. Here, multi-microsecond-long
all-atom molecular dynamics simulations of eight immune complexes
elucidate the subtleties of receptor (NKG2A/CD94)–ligand (HLA-E/β2m/peptide)
molecular recognition that mediate the NK cell protection from a geometric
and energetic perspective. We identify key differences in the interactions
between the receptor and ligand complexes, which are via an entangled
network of hydrogen bonds fine-tuned by the ligand-specific nonameric
peptide. We further reveal that the receptor protein NKG2A regulates
the NK cell activity, while its CD94 partner forms the majority of
the energetically important interactions with the ligand. This knowledge
rationalizes the atomistic details of the fundamental NK cell protection
mechanism and may enable a variety of opportunities in rational-based
drug discovery for diverse pathologies including viral infections
and cancer and elimination of senescent cells associated with potential
treatment of many age-related diseases.