Structural And Energetic Analysis of the p.Met1lle CFTR Variant

Abstract

Background: Cystic Fibrosis is a genetic disorder caused by mutations in the CFTR gene, leading to impaired epithelial ion transport and altered protein function.

Objective: This study evaluates the structural and functional impact of the p.Met1Ile (c.3G>A) CFTR variant using in-silico approaches.

Methodology: Comparative homology modeling and molecular docking were performed using Molecular Operating Environment (MOE). Wild-type and mutant CFTR structures were analyzed for docking scores, conformational stability, and protein–ligand interactions. Pathogenicity prediction tools were also applied to assess functional consequences of the variant.

Results: The wild-type CFTR showed higher binding affinity (S = −8.5677 kcal/mol) compared to the mutant (S = −7.8977 kcal/mol). The mutant exhibited altered conformational energy (E_conf = −541.4630 kcal/mol) and disrupted hydrogen bonding patterns, indicating reduced structural stability and ligand interaction.

Conclusion: The p.Met1Ile variant likely induces structural destabilization of CFTR, reducing ligand-binding efficiency. These findings support its potential pathogenic role and demonstrate the utility of computational docking in variant analysis.