Computational analysis of missense variants in MMP2 gene linked with Winchester syndrome and Nodulosis-Arthropathy-Osteolysis reveals structural shift in protein-protein and protein-ligand complexes

Abstract

Matrix metalloproteinases - 2 (MMP2) protein stimulates multiple processes involving the nervous system, vascularization, and metastasis. Mutations in MMP2 is linked to Winchester and Nodulosis-Arthropathy-Osteolysis (NAO) syndromes. In this extensive investigation, we performed a computational analysis of 114 missense Single Nucleotide Polymorphisms (SNPs) of MMP2 protein using various in-silico algorithms. A total of 21 highly deleterious and pathogenic missense SNPs (T86K, R146H, A167T, G216E, R252P, R252L D326V, D326Y, G346S, G367S, R368L, S396R, A408P, R482C, P517L, A522E, E525K, Y543C, Y552S, K579M, M598T) were identified that probably could alter the structural and functional configuration of MMP2 gene. Moreover, conservation analysis, protein stability, TM-score and RMSD calculation, protein structure prediction and superimposition, ligand binding site prediction, protein-protein interaction, protein-ligand, and protein-protein docking studies were carried out. ConSurf analysis showed seventeen missense variants in the highly conserved regions, which were predicted as highly deleterious and pathogenic by eight in-silico platforms. Furthermore, G367S and K579M showed a greater impact on stability, structural alterations, protein-ligand and protein-protein interactions. This study will help in developing target-dependent medication for diseases and could enhance the understanding of the significance of uncharacterized missense SNPs and their interrelation with the disease. This study also contemplates the computational perception into the high-risk missense SNPs on protein structural and functional configuration.