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Hang Yu, Wei Han, Wen Ma, and Klaus Schulten. Transient β-hairpin formation in α-synuclein monomer revealed by coarse-grained molecular dynamics simulation. Journal of Chemical Physics, 143:243142, 2015.

YU2015 Parkinson's disease is a common neurodegenerative disorder that originates from the intrinsically disordered peptide $\alpha$-synuclein aggregating into fibrils. It remains unclear how $\alpha$-synuclein monomers undergo conformational changes leading to aggregation and formation of fibrils characteristic for the disease. In the present study, we perform molecular dynamics simulations (over 150 $\mu$s in aggregated time) using a hybrid-resolution model, PACE, to characterize in atomic detail structural ensembles of wild type and mutant monomeric $\alpha$-synuclein in aqueous solution. The simulations reproduce structural properties of $\alpha$-synuclein characterized in experiments, such as secondary structure content, long-range contacts, chemical shifts and $^{3}$J(H$_{N}$H$_{C_{\alpha}}$)-coupling constants. Most notably, the simulations reveal that a short fragment encompassing region 38-53, adjacent to the non-Amyloid-$\beta$ component region, exhibits a high probability of forming a $\beta$-hairpin; this fragment, when isolated from the remainder of $\alpha$-synuclein, fluctuates frequently into its $\beta$-hairpin conformation. Two disease-prone mutations, namely A30P and A53T, significantly accelerate the formation of a $\beta$-hairpin in the stated fragment. We conclude that the formation of a $\beta$-hairpin in region 38-53 is a key event during $\alpha$-synuclein aggregation. We predict further that the G47V mutation impedes the formation of a turn in the $\beta$-hairpin and slows down $\beta$-hairpin formation, thereby retarding $\alpha$-synuclein aggregation.

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