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

Area of Science:

• Genetics and Molecular Biology
• Rheumatology
• Computational Biology

Background:

• Rheumatoid arthritis (RA) is a chronic autoimmune disease causing joint inflammation and degradation.
• Matrix metalloproteinase-9 (MMP9) is crucial in extracellular matrix remodeling and its elevated levels correlate with RA severity.

Purpose of the Study:

• To identify and characterize functional and pathogenic variants of the MMP9 gene.
• To assess the impact of these MMP9 variants on RA susceptibility and severity.

Main Methods:

• Utilized computational tools to identify deleterious non-synonymous single nucleotide polymorphisms (nsSNPs) in MMP9.
• Evaluated nsSNP conservation, protein structure/function impact, and stability using computational models (ERRAT, VERIFY3D, QMEAN).
• Performed molecular dynamics simulations, molecular docking, and gene-gene interaction analyses.

Main Results:

• Identified nine damaging missense nsSNPs in the MMP9 catalytic region, all highly conserved.
• Found that most mutations decreased protein stability and altered functional domains; Y262C lost a phosphorylation site.
• Molecular dynamics simulations showed increased instability in variants, with Y262C, P180L, G438A, and D434N exhibiting high RMSD values.

Conclusions:

• Pathogenic nsSNPs in MMP9 significantly affect its structure and function, contributing to RA.
• These findings are important for genetic screening in RA patients.
• Identified MMP9 variants may represent potential therapeutic targets for rheumatoid arthritis.