Structural and function impact of ERCC2 gene variants in Xeroderma pigmentosum: An integrative computational and docking analysis

Xeroderma pigmentosum (XP) is a rare inherited disorder that causes extreme sensitivity to sunlight, leading to early-onset skin lesions, eye complications, and a higher risk of developing tumors. The disease occurs due to defects in the DNA repair system, especially in the ERCC2 gene, which encodes a helicase enzyme essential for repairing ultraviolet-induced DNA damage. This study aimed to identify genetic variations in ERCC2 that may contribute to XP and to examine how these changes affect the structure and function of the encoded protein through detailed in-silico analysis. Nonsynonymous SNPs were collected from the dbSNP, UniProt, and Ensembl databases and evaluated using several prediction tools, including SIFT, PolyPhen-2, PredictSNP, PROVEAN, and MutPred2. Protein stability and structural alterations were assessed through I-Mutant 3.0, MUpro, DynaMut2, and SWISS-MODEL. Three highly deleterious and novel missense mutations R112H, R450C, and R658H were identified as potentially damaging. Structural modeling indicated that the R658H mutation disturbs hydrogen bonding and changes the α-helical arrangement near the ATP-binding site, possibly reducing helicase activity. Molecular docking and 100 ns molecular dynamics simulations with Loniflavone and Palbociclib showed stable binding interactions. Analyses of RMSD, RMSF, radius of gyration, hydrogen bonds, and MM-PBSA free energy confirmed stronger affinity for Loniflavone (−72.3 kJ mol−1) than Palbociclib (−64.8 kJ mol−1). Density Functional Theory further supported their chemical reactivity, while StopTox predicted low toxicity. The computationally derived insights in this study lay a strong foundation for subsequent in-vitro and in-vivo validation. While this work focuses on in-silico modeling and molecular simulation, the proposed drug-like candidates warrant future biochemical and cellular assays to confirm their biological relevance.