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

Abstract

Parkinson's disease, originating from the intrinsically disordered peptide α-synuclein, is a common neurodegenerative disorder that affects more than 5% of the population above age 85. It remains unclear how α-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 μs 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 α-synuclein in aqueous solution. The simulations reproduce structural properties of α-synuclein characterized in experiments, such as secondary structure content, long-range contacts, chemical shifts, and (3)J(HNHCα )-coupling constants. Most notably, the simulations reveal that a short fragment encompassing region 38-53, adjacent to the non-amyloid-β component region, exhibits a high probability of forming a β-hairpin; this fragment, when isolated from the remainder of α-synuclein, fluctuates frequently into its β-hairpin conformation. Two disease-prone mutations, namely, A30P and A53T, significantly accelerate the formation of a β-hairpin in the stated fragment. We conclude that the formation of a β-hairpin in region 38-53 is a key event during α-synuclein aggregation. We predict further that the G47V mutation impedes the formation of a turn in the β-hairpin and slows down β-hairpin formation, thereby retarding α-synuclein aggregation.

Triphala inhibits alpha-synuclein fibrillization and their interaction study by NMR provides insights into the self-association of the protein

“…This observation of a major random coil along with a minor anti-parallel b-sheet conformation of aSyn is consistent with earlier reports. 54,55 A clear structural transition from random coil to b-sheet was observed for aSyn aer 37 hours of incubation under brillating condition ( Fig. 2A).…”

(−)-Epigallocatechin-3-gallate (EGCG) inhibits fibrillation, disaggregates amyloid fibrils of α-synuclein, and protects PC12 cells against α-synuclein-induced toxicity

“…43 Here, from 1 H NMR spectroscopic results, we can nd that for inhibition of brillation, EGCG interacts with amino acid sites of Ile, Phe and Tyr which are different from Leu, His, Phe and Tyr for disaggregation of brils. Schulten et al 44 have found that residues from 36 to 55 in a-Syn adopt b-hairpin in b-sheet conformation by molecular dynamics simulation. Among those residues, Gly36, Leu38, Fig.…”

Multiple system atrophy: genetic risks and alpha-synuclein mutations

“…In particular, the A53T, A53E, and G51D mutations and SNCA gene triplications are associated with a more aggressive MSA-like clinical and pathological phenotype 45 (See Table 1 and Table 2 for details of the clinical and neuropathological features of SNCA mutations). Exactly why the codon 51 and 53 mutations in the SNCA gene lead to an MSA-like clinical and pathological phenotype is not known, but this is likely to be associated with the importance of this defined region and toxic gain of function of these protein changes ( Figure 1 ) 46 . From a clinical perspective, if there is any hint of a family history in patients with MSA, then the SNCA gene should be sequenced by using traditional Sanger 47 , gene panel, or exome sequencing and analysed for copy number changes 48 .…”

“…In the nuclear magnetic resonance structure of SNCA, the negatively charged C-terminal tail remains flexible and disordered (based on Yu et al . 46 ). The positions of point mutations associated with Parkinson’s disease are indicated with arrows and in pink.…”