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<p>Chronic Obstructive Pulmonary Disease (COPD) is a progressive respiratory condition influenced by intricate gene-environment interactions. Recent evidence suggests that dysregulation of the Sonic Hedgehog (SHH) signalling pathway contributes to airway epithelial remodelling and impaired lung repair. This research methodically identified and characterised harmful nonsynonymous single-nucleotide polymorphisms (nsSNPs) in critical Hedgehog pathway genes SHH, PTCH1, and SMO employing an integrative in silico and molecular simulation methodology. We got missense variants from NCBI dbSNP and checked them with SIFT, PolyPhen-2, PANTHER, PhD-SNP, PredictSNP2, SNAP2, and MetaSNP. I-Mutant2.0, MUpro, MutPred2, HOPE, ConSurf, SOPMA, ProtParam, and PolymiRTS were used to look at both functional and structural effects. Refined three-dimensional models underwent protein–protein docking (ClusPro) to assess SHH-PTCH1 interactions, succeeded by 100 ns molecular dynamics (MD) simulations utilising GROMACS to examine conformational stability.</p><p>Thirty high-confidence deleterious nsSNPs were identified, with the majority anticipated to diminish protein stability and impact conserved residues. Docking analyses showed that SHH N115K (− 2154.2&#xa0;kcal/mol), W117G (− 2077.9&#xa0;kcal/mol), and PTCH1 W235R (− 2030.8&#xa0;kcal/mol) had stronger interactions than the wild type (− 1830.6&#xa0;kcal/mol). On the other hand, SHH D88V and PTCH1 D259A had weaker binding. MD simulations demonstrated that the wild-type complex stabilised at ~ 1.0–1.1&#xa0;nm RMSD, while D88V (~ 1.2&#xa0;nm) and D259A (~ 2.2&#xa0;nm) exhibited increased structural deviation. Radius of gyration and SASA analyses indicated conformational expansion in V224E and pronounced compaction in D259A, accompanied by elevated residue-level fluctuations. Overall, these findings highlight functionally disruptive Hedgehog pathway variants that may contribute to COPD susceptibility and need experimental validation as potential genetic biomarkers.</p>

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Molecular modelling and simulation-based profiling of nsSNPs in hedgehog pathway genes linked to COPD susceptibility

  • 期刊论文

  • 发表日期：

    2026年3月30日

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  • Nidhi Mahajan,
  • Sidhartha Singh,
  • Vishal Chopra,
  • Kranti Garg,
  • Vaishnavi Gund,
  • Siddharth Sharma

摘要

Chronic Obstructive Pulmonary Disease (COPD) is a progressive respiratory condition influenced by intricate gene-environment interactions. Recent evidence suggests that dysregulation of the Sonic Hedgehog (SHH) signalling pathway contributes to airway epithelial remodelling and impaired lung repair. This research methodically identified and characterised harmful nonsynonymous single-nucleotide polymorphisms (nsSNPs) in critical Hedgehog pathway genes SHH, PTCH1, and SMO employing an integrative in silico and molecular simulation methodology. We got missense variants from NCBI dbSNP and checked them with SIFT, PolyPhen-2, PANTHER, PhD-SNP, PredictSNP2, SNAP2, and MetaSNP. I-Mutant2.0, MUpro, MutPred2, HOPE, ConSurf, SOPMA, ProtParam, and PolymiRTS were used to look at both functional and structural effects. Refined three-dimensional models underwent protein–protein docking (ClusPro) to assess SHH-PTCH1 interactions, succeeded by 100 ns molecular dynamics (MD) simulations utilising GROMACS to examine conformational stability.

Thirty high-confidence deleterious nsSNPs were identified, with the majority anticipated to diminish protein stability and impact conserved residues. Docking analyses showed that SHH N115K (− 2154.2 kcal/mol), W117G (− 2077.9 kcal/mol), and PTCH1 W235R (− 2030.8 kcal/mol) had stronger interactions than the wild type (− 1830.6 kcal/mol). On the other hand, SHH D88V and PTCH1 D259A had weaker binding. MD simulations demonstrated that the wild-type complex stabilised at ~ 1.0–1.1 nm RMSD, while D88V (~ 1.2 nm) and D259A (~ 2.2 nm) exhibited increased structural deviation. Radius of gyration and SASA analyses indicated conformational expansion in V224E and pronounced compaction in D259A, accompanied by elevated residue-level fluctuations. Overall, these findings highlight functionally disruptive Hedgehog pathway variants that may contribute to COPD susceptibility and need experimental validation as potential genetic biomarkers.