Structural and mechanistic insights into IL2RG-associated immunodeficiency through computational approaches

Interleukin-2 receptor γ chain (IL2RG, CD132) act as a signaling subunits for various cytokine receptors, required for lymphocyte growth and maturation. Genetic variants within the IL2RG gene are associated with X-linked Severe Combined Immunodeficiency (X-SCID) disease. This study uses an in-silico method to investigate the structural and functional impacts of two IL2RG variants, Trp240Arg (W240R) and Arg226Cys (R226C), located in the extracellular domain, a region important for receptor stability. Homology modeling was generated for Wild-Type (WT) and Variant IL2RG structures and subsequently analyzed through Molecular Dynamics (MD) simulations and protein-protein docking utilizing IL-2 and IL-21 cytokines. MD simulations showed that WT-IL2RG remained stable, whereas its variant exhibited structural instability. W240R is disrupted by increased solvent exposure and reduced compactness. The IL-2 binding caused structural alterations in the WT complex in cytokine-bound states, whereas R226C reduced hydrogen bonds to decrease binding, and W240R increased flexibility to destabilize the interface. The WT complex exhibited consistent hydrogen bonding and was the most stable for IL-21, whereas both variants displayed weaker interactions and fluctuations. Further, the binding free energy Molecular Mechanics-Poisson Boltzmann Surface Area (MM/PBSA) analysis confirmed that WT complexes had better binding (IL-2: -40.87 kJ/mol; IL-21: -45.88 kcal/mol) compared to R226C (-35.42, -34.67 kcal/mol) and W240R (-29.54, -33.30 kcal/mol). The study reveals that Trp240Arg and Arg226Cys variants in IL2RG negatively affect cytokine-receptor interactions, lower binding energetics, and disturb the structural integrity of IL2RG, shedding light on the mechanisms underlying IL2RG-associated immunodeficiency disorders.