Elucidating the functional impact of G137V and G144R variants in Maroteaux Lamy's Syndrome by Molecular Dynamics Simulation

Mucopolysaccharidoses VI (Maroteaux Lamy syndrome) is a metabolic disorder due to the loss of enzyme activity of N-acetyl galactosamine-4-sulphatase arising from mutations in the ARSB gene. The mutated ARSB is the origin for the accumulation of GAGs within the lysosome leading to severe growth deformities, causing lysosomal storage disease. The main focus of this study is to identify the deleterious variants by applying bioinformatics tools to predict the conservation, pathogenicity, stability, and effect of the ARSB variants. We examined 170 missense variants, of which G137V and G144R were the resultant variants predicted detrimental to the progression of the disease. The native along with G137V and G144R structures were fixed as the receptors and subjected to Molecular docking with the small molecule Odiparcil to analyze the binding efficiency and the varied interactions of the receptors towards the drug. The interaction resulted in similar docking scores of - 7.3 kcal/mol indicating effective binding and consistent interactions of the drug with residues CYS117, GLN118, THR182, and GLN517 for native, along with G137V and G144R structures. Molecular Dynamics were conducted to validate the stability and flexibility of the native and variant structures on ligand binding. The overall study indicates that the drug has similar therapeutic towards the native and variant based on the higher binding affinity and also the complexes show stability with an average of 0.2 nm RMS value. This can aid in the future development therapeutics for the Maroteaux Lamy syndrome.