Molecular Dynamics Study to Investigate the Dimeric Structure of the Full-Length α-Synuclein in Aqueous Solution

The mechanisms of dimerization of a-synuclein from full-length monomers and their structural features have been investigated through molecular dynamics simulations in this study. The dimerization of alpha-syn plays a critical role in the fibrillogenesis mechanism and could initiate and trigger a-syn to aggregate by conformational transforming. According to the alignment between three regions of a-syn monomer, eight diverse starting structures have been constructed. However, only five configurations show the dimeric structures, and the detailed properties of three dimers of them are discussed. During the simulations, both identical a-syn peptides (P1 and P2) of these three dimers reduce the high contents of a-helix from their native folded structures, while the contents of beta-sheet increase. Antiparallel beta-hairpin motifs within the a-syn peptide are formed by intramolecular interactions. The beta-hairpin regions are adjacent to the nonamyloid beta component (NAC) of a-syn, and these structural features are consistent with the experimental observation. Moreover, intermolecular beta-sheets also are generated between P1 and P2 through hydrogen bonding interactions. The dimers produce both intramolecular beta-hairpin and intermolecular beta-sheet characters; the former is presented in monomer and oligomer of a-syn, and the latter occurs in the fibril structure. The simulations also show several other interactions such as hydrophobic interactions and salt-bridges, which would contribute to making the a-syn dimers more stable with the aforementioned effects. The results may pave the way to design small molecules to inhibit the dimerization in order to block the aggregation of a-syn in the future.