Abstract

The interaction between Natural Killer (NK) cell receptors and Major Histocompatibility Complex (MHC) Class I molecules is a critical checkpoint in immune surveillance, regulating the cytotoxic activity of NK cells. Specifically, the activating receptor **KIR2DS4** recognizes certain allotypes of the human leukocyte antigen (HLA) class I molecule, **HLA-C**, with the nature of the presented peptide being a key determinant of binding affinity. This study aimed to computationally predict the molecular details of the interaction between KIR2DS4 and the **HLA-C\*05-peptide complex**, a pairing implicated in various immune responses. Using advanced *in silico* modeling techniques, including molecular docking and dynamics simulations, we investigated the structural interface and the influence of the peptide sequence on the complex stability. Our predictions suggest that the interaction is highly dependent on specific peptide residues, particularly those located at the C-terminus, which form critical contact points with the KIR2DS4 binding groove. The predicted binding mode highlights the importance of the cell surface membrane components in mediating immune recognition. These findings provide a structural basis for understanding the immunogenetics of the KIR2DS4/HLA-C\*05 axis and offer valuable insights for therapeutic strategies targeting NK cell function.