We report molecular dynamics simulations of two modifications to α-Synuclein, namely A53T mutation and phosphorylation at Ser129, which have been observed in Parkinson's disease patients. Both modifications are close to known metal binding sites, so as well as each modified peptide we also study Cu(II) bound to N-terminal and C-terminal residues. We show that A53T is predicted to cause increased β-sheet content of the peptide, with a persistent β-hairpin between residues 35-55 particularly notable. Phosphorylation has less effect on secondary structure but is predicted to significantly increase the size of the peptide, especially when bound to Cu(II), which is ascribed to reduced interaction of C-terminal sequence with central non-amyloid component. In addition, estimate of binding free energy to Cu(II) indicates A53T has little effect on metal-ion affinity, whereas phosphorylation markedly enhances the strength of binding. We suggest that the predicted changes in spatial extent and secondary structure of α-Synuclein may have implications for aggregation into Lewy bodies.
Keywords: Copper; Molecular dynamics; Mutation; PTM; Parkinson's disease; Synuclein.
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