2658-6533Research Results in Biomedicine2658-653310.18413/2658-6533-2025-11-2-0-43769Pharmacology<strong><em>In-silico </em></strong><strong>insights into &alpha;-Synuclein mediated pathology of Parkinson&rsquo;s disease using molecular docking and molecular dynamics simulation studies</strong><br /> &nbsp;<strong><em>In-silico </em></strong><strong>insights into &alpha;-Synuclein mediated pathology of Parkinson&rsquo;s disease using molecular docking and molecular dynamics simulation studies</strong><br /> &nbsp;GrewalAnnuGrewalAnnuagrewal113@gmail.comSharmaRiddhiSharmaRiddhiriddhi23.sharma@gmail.comSheokandDeepakSheokandDeepakdpk.sheo@gmail.comKumarPawanKumarPawanpatriotpawan@gmail.comSainiVandanaSainiVandanavandanas64@gmail.comKumarAjitKumarAjitakumar.cbt.mdu@gmail.com202511200

Background: The precise cause of neuronal loss in Parkinson&#39;s disease (PD) is multifactorial, involving genetic and environmental factors. Genetic mutations, affecting many proteins such as &alpha;-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: &alpha;-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 &alpha;-Synuclein. The SNPs &ndash; 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) &alpha;-Synuclein aggregates. Also, G51D and E46K mutated oligomeric structures of &alpha;-Synuclein showed twisted morphologies. Molecular dynamics simulation studies provided evidence for the stabilized conformation of the decameric form of wild-type &alpha;-Synuclein. Conclusion: The study paves a good platform for further investigation to consider the decameric form of &alpha;-Synuclein protein as a target for PD therapeutics

Background: The precise cause of neuronal loss in Parkinson&#39;s disease (PD) is multifactorial, involving genetic and environmental factors. Genetic mutations, affecting many proteins such as &alpha;-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: &alpha;-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 &alpha;-Synuclein. The SNPs &ndash; 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) &alpha;-Synuclein aggregates. Also, G51D and E46K mutated oligomeric structures of &alpha;-Synuclein showed twisted morphologies. Molecular dynamics simulation studies provided evidence for the stabilized conformation of the decameric form of wild-type &alpha;-Synuclein. Conclusion: The study paves a good platform for further investigation to consider the decameric form of &alpha;-Synuclein protein as a target for PD therapeutics

Parkinson’s diseasehub-proteinα-Synucleinsingle nucleotide polymorphismsaggregationoligomerizationprotein-protein dockingmolecular dynamics simulationParkinson’s diseasehub-proteinα-Synucleinsingle nucleotide polymorphismsaggregationoligomerizationprotein-protein dockingmolecular dynamics simulation

the authors wish to thank UGC New Delhi for providing JRF to AG and the High-performance computing (HPC) facility &lsquo;Param Smriti&rsquo;, NABI, Mohali for the super-computational facility

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