Examining the Atypical Structure Adopted by the 37-51 Segment of α-synuclein in the Early Stage of Aggregation

The aggregation of α-synuclein into insoluble filaments is a hallmark of Parkinson’s disease. Upon membrane binding, α-synuclein adopts a helical conformation, whereas during neurodegeneration it misfolds and aggregates into β-sheet-rich structures. However, the factors that trigger the misfolding and aggregation remain poorly understood. In this study, coarse-grained molecular dynamics simulations are used to characterize the structural ensembles of α-synuclein monomers and dimers at atomic resolution during the early stage of aggregation, covering an effective timescale of 29.7 ms. The simulations reveal that a short sequence spanning residues 37-51 predominantly adopts three distinct conformations: β-hairpin, braid, and random coil. Here, focus is placed on a braid conformation, which, to the best of our knowledge, has not been reported previously in either experimental or computational studies. Although we could not definitively rule out the possibility that the coarse-grained force field overestimates the stability of the braid, two all-atom simulations demonstrated that this structure is sterically feasible and metastable. Furthermore, in monomers, the braid appears to hinder the formation of long-range intramolecular interactions, leaving the N-terminus, NAC (non-amyloid-β component) region, and C-terminus solvent-exposed and potentially facilitating fibril nucleation. In dimers, however, the braid appears to impede intermolecular contacts, especially homotypic intermolecular interactions, thereby slowing aggregation. Upon unfolding of the braid structure, intermolecular contacts, including homotypic interactions, increase noticeably.