Computational investigation on the effects of H50Q and G51D mutations on the α-Synuclein aggregation propensity.
The aggregation of α-synuclein is linked directly to the histopathology of Parkinson's disease (PD). However, several missense mutations present in the α-synuclein gene (SNCA) have been known to be associated with PD. Several studies have highlighted the effect of SNCA mutations on the α-synuclein aggregation, but their pathological roles are not completely established. In this study, we have focused on the effects of the recently discovered α-synuclein missense mutants (H50Q and G51D) on the aggregation using computational approaches. We performed all atom molecular dynamics (MD) simulation on these mutants and compared their conformational dynamics with Wild-Type (WT) α-synuclein. We noticed the solvent accessible surface area (SASA), radius of gyration, atomic fluctuations, and beta strand content to be higher in H50Q than G51D and WT. Using PDBSum online server; we analyzed the inter-molecular interactions that drive the association of monomeric units of H50Q, WT, and G51D in forming the respective homo-dimer. We noticed the interface area, number of interacting residues and binding free energy to be higher for H50Q homo-dimer than the WT and G51D homo-dimers. Our findings in this study suggest that in comparison to WT and G51D, H50Q mutation to have a positive effect on increasing the α-synuclein aggregation propensity. Hence, we see that H50Q and G51D mutation show conflicting effect on the aggregation propensity of α-synuclein.
['Sanjeev|Airy|A|', 'Mattaparthi|Venkata Satish Kumar|VSK|http://orcid.org/0000-0002-5238-753X']
D019943:Amino Acid Substitution D006801:Humans D008958:Models, Molecular D009154:Mutation D066329:Protein Aggregates D066263:Protein Aggregation, Pathological D011485:Protein Binding D055503:Protein Multimerization D021281:Quantitative Structure-Activity Relationship D051844:alpha-Synuclein
aggregation missense AMBER Parkinson’s disease fibrillation