All-Atom Simulations Reveal a Key Interaction Network in the HLA-E/NKG2A/CD94 Immune Complex Fine-Tuned by the Nonameric Peptide.
Eva PrašnikarAndrej PerdihJure BorišekPublished in: Journal of chemical information and modeling (2021)
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.
Keyphrases
- nk cells
- molecular dynamics simulations
- induced apoptosis
- cell cycle arrest
- drug discovery
- single cell
- molecular dynamics
- healthcare
- signaling pathway
- immune response
- binding protein
- endoplasmic reticulum stress
- cell death
- air pollution
- squamous cell carcinoma
- gene expression
- molecular docking
- dna methylation
- risk assessment
- oxidative stress
- genome wide
- hiv infected
- combination therapy
- lymph node metastasis