Structural and Functional Impact of Damaging Nonsynonymous Single Nucleotide Polymorphisms (nsSNPs) on Human VPS35 Protein Using Computational Approaches.

Parkinson's disease is the second most common progressive neurodegenerative movement disorder. Mutations in retromer complex subunit and VPS35 represent the second most common cause of late-onset familial Parkinson's disease. The mutation in VPS35 can disrupt the normal protein functions resulting in Parkinson's disease. The aim of this study was the identification of deleterious missense Single Nucleotide Polymorphisms (nsSNPs) and their structural and functional impact on the VPS35 protein. In this study, several insilico tools were used to identify deleterious and disease-associated nsSNPs. 3D structure of VPS35 protein was constructed through MODELLER 9.2, normalized using FOLDX, and evaluated through RAMPAGE and ERRAT whereas, FOLDX was used for mutagenesis. 25 ligands were obtained from literature and docked using PyRx 0.8 software. Based on the binding affinity, five ligands i.e., PG4, MSE, GOL, EDO, and CAF were further analyzed. Molecular Dynamic simulation analysis was performed using GROMACS 5.1.4, where temperature, pressure, density, RMSD, RMSF, Rg, and SASA graphs were analyzed. The results showed that the mutations Y67H, R524W, and D620N had a structural and functional impact on the VPS35 protein. The current findings will help in appropriate drug design against the disease caused by these mutations in a large population using in-vitro study.