Decoding pathogenic MMP9 variants in rheumatoid arthritis using computational and molecular dynamics approaches

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint inflammation, pain, swelling, and stiffness, with matrix metalloproteinase-9 (MMP9) playing a critical role in extracellular matrix remodelling and joint degradation. Elevated MMP9 levels are closely associated with RA severity and progression. This study aimed to identify and characterize functional and pathogenic variants of the MMP9 gene and assess their impact on RA susceptibility and severity. Various computational tools were used to identify deleterious non-synonymous single nucleotide polymorphisms (nsSNPs). These nsSNPs were further evaluated for their conservation profiles, influence on protein structure, function, and phenotypic stability. Models for all the mutant and wild type were generated and validated by ERRAT, VERIFY3D and QMEAN. Further, molecular dynamics simulations, molecular docking and gene-gene interactions were analysed. Nine damaging missense nsSNPs within the MMP9 catalytic region were identified, all of which were highly conserved, with Y262C notably resulting in the loss of a phosphorylation site. Most mutations were associated with decreased protein stability, and HOPE analysis revealed their localization in essential functional domains of MMP9. MD simulations indicated greater structural instability in these variants compared to the wild type, with Y262C, P180L, G438A, and D434N exhibiting the highest root-mean-square deviation (RMSD) values. Gene-gene interaction analysis further emphasized the significant role of MMP9 in RA-related pathways. This study offers key insights into pathogenic nsSNPs affecting MMP9 structure and function, highlighting their importance in genetic screening and potential therapeutic strategies for RA.