Background: Aggregation of Human α-synuclein protein into well-ordered amyloid fibrils
is critical at the onset of Parkinson’s disease (PD), a progressive and irreversible neurodegenerative
disorder. In the recent past, the importance of tyrosine residues in the fibrillation process
of α-synuclein has been highlighted but their definite role in the early events of fibrillation is not
Objective: To understand the role of Tyr residues on the early events of α-synuclein fibrillation process.
Methodology: We have used the all the atom molecular dynamics simulation and investigated the
conformational dynamics of wild-type (WT) and the three modelled Tyr mutants (Y39A, Y133A,
and Y (125,133,136) A) of α-synuclein.
Results: Among the WT and the mutants, we observed Y(125, 133, 136)A and Y133A to have lesser
number of hydrophobic contacts between the residues in the N- and C-terminal regions, exhibiting a
differing folding pattern and conformation that has the ability to delay the aggregation propensity of
α-synuclein. We also found that Tyr residue at position 133 is primarily important to drive the intramolecular
interactions and subsequent fibrillation process.
Conclusion: Therefore, our findings in this study suggest that targeting the Tyr residue at the position
133 may provide better solution to significant delay in the early stage of aggregation in α-