STRUCTURAL MODELING AND FUNCTIONAL PREDICTION OF IFN-Y GENE VARIANTS

IFN-γ is a key immunomodulatory cytokine primarily secreted by activated T lymphocytes, NK cells, NKT cells, and dendritic cells. The IFN-γ protein is encoded by the IFNG gene located on chromosome 9q14.3 and plays a central role in host immune responses. The current study employed an integrated computational approach to predict deleterious missense SNPs of the IFN-γ gene. These variants potentially disrupt the structural integrity and biological activity of IFN-γ, contributing to aberrant immune responses implicated in tumorigenesis and chronic inflammation. To assess the functional consequences of these mutations, molecular docking analyses were conducted. Through comprehensive screening, 12 deleterious nsSNPs were identified, localized within non-synonymous regions. SOPMA revealed that the IFN-γ protein is predominantly α-helical, constituting about 66.27% of the total secondary structure. Our results show high disorder scores for the G161R, R152Q, M1L, and A164S mutants, suggesting a loss of structural order, which may negatively impact protein function. Structural modeling was performed using AlphaFold, followed by validation with the SAVES v6.0 server. K28T, Y37C, and Y76F induced marked conformational changes involved in receptor binding, as evidenced by high RMSD values. Our results emphasize Laminin, Tamoxifen, Fulvestrant, Melanin, Parecoxib, and Rofecoxib. Both Laminin and Melanin demonstrated strong binding affinities with native and mutant IFN-γ structures, engaging crucial residues such as Phe115, Glu116, Phe105, and Val73. These residues are crucial for ligand binding and cytokine function, highlighting their therapeutic importance. Our findings provide insights for the development of targeted therapies for IFN-γ-related disorders, including autoimmune diseases, cancer, and infectious conditions. The novelty of this study lies in its comprehensive analysis of mutant IFN-γ forms, paving the way for precision medicine approaches tailored to genetically diverse populations. Further experimental validation is necessary to substantiate these findings and evaluate their clinical significance.