A computational approach to analyse the amino acid variants of GLB1 protein causing GM1 Gangliosidosis

• Published in: Metabolic brain disease Vol. 36; no. 3; pp. 499 - 508
• Main Authors: Priyanka, K., Madhana Priya, N., Magesh, R.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01-03-2021; Springer Nature B.V
• Subjects: Affinity; Amino acid sequence; Amino acids; Binding sites; Biochemistry; Biomedical and Life Sciences; Biomedicine; Computational neuroscience; Gangliosidosis; Glycolipids; Lysosomal storage diseases; Metabolic Diseases; Molecular docking; Molecular dynamics; Mutation; Neurology; Neurosciences; Oncology; Original Article; Pathogenicity; Pathogens; Phenotypes; Protein structure; Proteins; Spinal cord; Stability analysis; Trajectory analysis; Molecular dynamics; Amino acid variants; Miglustat; GLB1; GM1 gangliosidosis; Molecular docking
• ISSN: 0885-7490; 1573-7365
• DOI: 10.1007/s11011-020-00650-y

Lysosomal storage diseases comprise different forms of autosomal recessive disorders from which GM1 gangliosidosis has categorized by the accumulation of complex glycolipids associated with a range of progressive neurologic phenotypes. GM1 gangliosidosis is an inherited disorder that progressively destroys nerve cells (neurons) in the brain and spinal cord. GM1 has three main types of onsets, namely infantile (type I), juvenile (type II), and adult (type III) forms. This study provides a series of computational methods that examine the mutations that occurred in GLB1 protein. Initially, the mutational analysis started with 689 amino acid variants for a sequence-based screening and it was done with quite a few
In-silico
tools to narrow down the most significant variants by utilizing the standard tools; namely, Evolutionary analysis (77 variants), Pathogenicity prediction (44 variants), Stability predictions (30 variants), Biophysical functions (19 variants) and according to the binding site of protein structure with PDB ID 3THC, seven variants (Y83D, Y83H, Y270S, Y270D, W273R, W273D, and Y333H) were narrowed down. Structure based analysis was performed to understand the interacting profile of the native protein and variants with Miglustat; which is the currently used FDA drug as an alternative to enzyme replacement therapy. Molecular Docking study was done to analyze the protein interaction with Miglustat (ligand), as a result native (3THC) structure had a binding affinity of −8.18 kcal/mol and two variant structures had an average binding affinities of −2.61 kcal/mol (Y83D) and − 7.63 kcal/mol (Y270D). Finally, Molecular Dynamics Simulation was performed to know the mutational activity of the protein structures on Miglustat for 50,000 ps. The Y83D variant showed higher deviation than native protein and Y270D in all trajectory analysis. The analysis was done to the protein structures to check the structural variations happened through simulations. This study aids to understand the most deleterious mutants, the activity of the drug to the protein structure and also gives an insight on the stability of the drug with the native and selected variants.