Functional Characterization of IL-17F Polymorphism Using Computational Tools

Abstract

Background: Obesity is a complex disorder influenced by both environmental exposures and genetic predisposition, with inflammatory cytokines playing a central role. Interleukin-17F (IL-17F), a pro-inflammatory mediator, has been linked to multiple immune-related diseases, but the contribution of its coding variants to disease susceptibility remains poorly defined. Objective: This study aimed to identify potentially deleterious nonsynonymous single-nucleotide polymorphisms (nsSNPs) in IL-17F and evaluate their structural and functional impact using computational tools. Methods: Missense variants were retrieved from public databases and screened with prediction algorithms (SIFT, PolyPhen-2, PhD-SNP, SNPs&GO, and PANTHER). Stability was assessed using I-Mutant 3.0 and MUpro, functional effects with MutPred, and evolutionary conservation with ConSurf. Three-dimensional protein structures were modeled by I-TASSER and compared with TM-align. Gene and protein interaction networks were examined using GeneMANIA and STRING, while phosphorylation and ubiquitination sites were predicted with GPS/NetPhos and BDM-PUB. Results: From 2,230 IL-17F variants, 158 were missense substitutions. Cross-tool consensus highlighted 23 nsSNPs with deleterious potential. Most substitutions reduced protein stability, particularly R77S, P81S, and V155G. MutPred scores indicated that cysteine substitutions at positions 107 and 152 were especially disruptive (>0.91). ConSurf revealed that the majority of these variants occur at conserved residues, while structural modeling demonstrated RMSD deviations up to 3.2 Å, consistent with conformational disturbance. Predicted phosphorylation and ubiquitination hotspots suggested that some variants may also alter regulatory post-translational modifications. Conclusion: Computational analysis identified multiple IL-17F nsSNPs likely to compromise protein structure and function. These findings provide a prioritized set of variants for experimental validation and genetic association studies, contributing to understanding the role of IL-17F in obesity and related inflammatory conditions.