Elucidating the mutational impact in causing Niemann-Pick disease type C: an in silico approach.
Priyanka KannanMadhana Priya Nanda KumarNithya RathinamThirumal Kumar DMagesh RPublished in: Journal of biomolecular structure & dynamics (2022)
Niemann-Pick disease type C is a rare autosomal recessive of lysosomal storage disorder characterized by impaired intracellular lipid transport and has a tendency to accumulate the fatty acids and glycosphingolipids in a variety of neurovisceral tissues. This work includes computational tools to deciphere the mutational effect in NPC protein. The study initiated with the collection of 471 missense mutations from various databases, which were then analyzed using computational tools. The mutations (G549V, F703S, Q775P and L1244P) were said to be disease associated, altering the biophysical properties, in highly conserved regions and reduces the stability using several in silico methods and were subjected to molecular docking analysis. To analyze the ligand (Itraconazole: a small molecule of antifungal drug class, which is known to inhibit cholesterol export from lysosomes) activity Molecular docking study was performed for all the complex proteins. The average binding affinity was taken and found to be -10.76 kcal/mol (native) and -11.06 kcal/mol (Q775P was located in transmembrane region IV which impacts the sterol-sensing domain of the NPC1 protein and associated with a severe infantile neurological form). Finally, molecular dynamic simulation was performed in duplicate and trajectories were built for the backbone of the RMSD, RMSF, the number of intramolecular hydrogen bonds, the radius of gyration and the SSE percent for both the complex proteins. This work contributes to understand the effectiveness and may provide an insight on the stability of the drug with the complex variant structures. Communicated by Ramaswamy H. Sarma.
Keyphrases
- molecular docking
- molecular dynamics simulations
- small molecule
- fatty acid
- protein protein
- randomized controlled trial
- depressive symptoms
- intellectual disability
- binding protein
- candida albicans
- systematic review
- high resolution
- autism spectrum disorder
- gene expression
- emergency department
- transcription factor
- quantum dots
- brain injury
- adverse drug
- mass spectrometry
- big data
- dna binding
- artificial intelligence