Structural Alignment and Interaction Mapping of Fibrosis Associated Proteins: An Advanced Bioinformatics Study

Abstract

This study investigates the impact of social media on the development of communicative compensation strategies among Lung fibrosis, particularly idiopathic pulmonary fibrosis (IPF), involves chronic, progressive scarring of lung tissue driven by dysregulated extracellular matrix (ECM) remodelling and persistent fibroblast activation. This study presents a comprehensive bioinformatics investigation of the structural biology and protein–protein interaction (PPI) mapping of six key fibrosis associated proteins: MMP2, MMP9, TGFB1, ACTA2, FBLN1, and COL1A1. Three dimensional structural superimposition was performed using US align and MM align to identify conserved domains, TM scores, and RMSD values across all pairwise and multi way combinations. An expanded structural alignment matrix covering ten pairwise combinations reveals TM scores ranging from 0.18 (ACTA2–COL1A1; distinct folds) to 0.48 (MMP9–MMP2; shared gelatinase superfamily), with highest inter family similarity between FBLN1 and TGFB1 (TM score = 0.34), attributable to the structural homology between fibulin cbEGF repeats and TGF β finger loops a finding with implications for LTBP1 mediated TGF β sequestration in the ECM. PPI networks constructed using STRING v12 (2025) identify TGFB1 as the dominant signalling hub (degree = 38; MCC rank = 1), forming a dense interaction triangle with MMP2 and MMP9 governing ECM degradation. KEGG and Disease Ontology enrichment analysis confirms significant involvement of these proteins in the TGF β signalling pathway (hsa04350), ECM receptor interaction (hsa04512), regulation of actin cytoskeleton (hsa04810), and pathways shared with oncogenic processes (Proteoglycans in cancer, hsa05205). A detailed domain architecture analysis of all six proteins identifies key fibrosis relevant structural features including the MMP catalytic Zn²⁺ binding HEXGHXXGXXH motif, the TGF β cystine knot growth factor fold, the FBLN1 calcium binding EGF repeat (cbEGF) arrays, and the COL1A1 Gly X Y triple helix repeat with 4 hydroxyproline water bridges. Virtual screening analysis against the six hub proteins identifies druggable cavities and lead compounds including fresolimumab, galunisertib, marimastat, halofuginone, BAPN, and nintedanib. These structural and interaction based insights provide a rigorous mechanistic framework for the molecular architecture of lung fibrosis and constitute a high quality foundation for anti fibrotic drug design, biomarker validation, and experimental follow up.