Computational analysis and molecular dynamics insights into deleterious SNPs of the HFE gene

Mutations in the HFE gene, especially non-synonymous single-nucleotide polymorphisms (nsSNPs), are strongly associated with hemochromatosis, an autosomal recessive disorder characterized by intracellular iron overload, a key feature of tumor development. This study examined the structural and functional effects of deleterious nsSNPs in the HFE gene using bioinformatics tools, gene interaction analyses, molecular docking, molecular dynamics (MD) simulations, and assessments of clinical relevance. Functional analyses identified nine deleterious nsSNPs, including C282Y, L183P, and Q283P, which disrupted disulfide bonds, hydrogen bonds, and hydrophobic interactions, destabilizing the protein. Conservation analysis revealed these mutations occur in highly conserved regions, emphasizing their structural and functional importance. Notably, five nsSNPs (R224Q, R224W, I235T, C282Y, Q283P) within the Ig-like C1-type domain were associated with cancer. Gene interaction analyses showed HFE-related genes are linked to immunity and iron balance. Variants in interacting genes, such as HJV, TFR2, TFRC, and B2M, may influence iron disorders, infection risk, and inflammation. Molecular docking showed reduced interface interactions for the C282Y mutant and altered binding to transferrin receptor 1 (TfR1), potentially destabilizing the HFE-TfR1 complex. MD simulations highlighted key differences, with the mutant showing higher RMSD, decreased compactness (Rg), increased flexibility (RMSF), and greater solvent exposure (SASA), confirming destabilization. Furthermore, HFE expression varied across cancers, with elevated levels in twelve tumor types. Higher expression correlated with better survival in breast and gastric cancers but poorer outcomes in lung cancer. These findings highlight how deleterious nsSNPs, especially C282Y, disrupt HFE structure and function, offering insights into disease mechanisms and guiding therapeutic strategies.