Background: The precise cause of neuronal loss in Parkinson's disease (PD) is multifactorial, involving genetic and environmental factors. Genetic mutations, affecting many proteins such as α-Synuclein, Leucine-rich repeat kinase 2, and Parkin, have been implicated in sporadic and familial cases, shedding light on key molecular pathways involved in disease pathogenesis. The aim of the study: The present in-silico study was undertaken to study the hub protein responsible for PD pathogenesis and the effect of mutations on its pathophysiology. Materials and methods: Pathological proteins were selected using the KEGG database, and their protein-protein interaction mapping was done using the STRING database, followed by network merging and hub-protein identification using Cytoscape 3.9.1. Protein-protein docking studies were performed to study the pathology of identified hub-protein using Hex 8.00, and their validation was done by performing molecular dynamics simulation studies using GROMACS v2020.1. Results: α-Synuclein was identified as the hub protein responsible for PD pathology and studied for its pathological mechanism of aggregation in wild-type and mutated form (A53T, E46K, H50Q, A53E and G51D) using protein-protein docking studies. On decamerization, 4 of 5 studied SNPs (A53T, A53E, G51D and H50Q) showed better binding affinities in the VI-IV combination, while E46K showed better binding affinity in the VII-III combination than wild-type α-Synuclein. The SNPs – A53T, E46K and H50Q, demonstrated lower binding energies while 2 SNPs (A53E and G51D) displayed higher binding energies in decameric form than wild-type (WT) α-Synuclein aggregates. Also, G51D and E46K mutated oligomeric structures of α-Synuclein showed twisted morphologies. Molecular dynamics simulation studies provided evidence for the stabilized conformation of the decameric form of wild-type α-Synuclein. Conclusion: The study paves a good platform for further investigation to consider the decameric form of α-Synuclein protein as a target for PD therapeutics
Background: The precise cause of neuronal loss in Parkinson's disease (PD) is multifactorial, involving genetic and environmental factors. Genetic mutations, affecting many proteins such as α-Synuclein, Leucine-rich repeat kinase 2, and Parkin, have been implicated in sporadic and familial cases, shedding light on key molecular pathways involved in disease pathogenesis. The aim of the study: The present in-silico study was undertaken to study the hub protein responsible for PD pathogenesis and the effect of mutations on its pathophysiology. Materials and methods: Pathological proteins were selected using the KEGG database, and their protein-protein interaction mapping was done using the STRING database, followed by network merging and hub-protein identification using Cytoscape 3.9.1. Protein-protein docking studies were performed to study the pathology of identified hub-protein using Hex 8.00, and their validation was done by performing molecular dynamics simulation studies using GROMACS v2020.1. Results: α-Synuclein was identified as the hub protein responsible for PD pathology and studied for its pathological mechanism of aggregation in wild-type and mutated form (A53T, E46K, H50Q, A53E and G51D) using protein-protein docking studies. On decamerization, 4 of 5 studied SNPs (A53T, A53E, G51D and H50Q) showed better binding affinities in the VI-IV combination, while E46K showed better binding affinity in the VII-III combination than wild-type α-Synuclein. The SNPs – A53T, E46K and H50Q, demonstrated lower binding energies while 2 SNPs (A53E and G51D) displayed higher binding energies in decameric form than wild-type (WT) α-Synuclein aggregates. Also, G51D and E46K mutated oligomeric structures of α-Synuclein showed twisted morphologies. Molecular dynamics simulation studies provided evidence for the stabilized conformation of the decameric form of wild-type α-Synuclein. Conclusion: The study paves a good platform for further investigation to consider the decameric form of α-Synuclein protein as a target for PD therapeutics
the authors wish to thank UGC New Delhi for providing JRF to AG and the High-performance computing (HPC) facility ‘Param Smriti’, NABI, Mohali for the super-computational facility.