Transient β-hairpin formation in α-synuclein monomer revealed by coarse-grained molecular dynamics simulation

Parkinson's disease, originating from the intrinsically disordered peptide alpha-synuclein, is a common neurodegenerative disorder that affects more than 5% of the population above age 85. 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 180 mu s in aggregated time) using a hybrid-resolution model, Proteins with Atomic details in Coarse-grained Environment (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(HNHC 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. (C) 2015 AIP Publishing LLC.