Wild-Type <i>α</i>-Synuclein and Variants Occur in Different Disordered Dimers and Pre-Fibrillar Conformations in Early Stage of Aggregation.

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α-Synuclein is a 140 amino-acid intrinsically disordered protein mainly found in the brain. Toxic α-synuclein aggregates are the molecular hallmarks of Parkinson's disease. In vitro studies showed that α-synuclein aggregates in oligomeric structures of several 10th of monomers and into cylindrical structures (fibrils), comprising hundred to thousands of proteins, with polymorphic cross-β-sheet conformations. Oligomeric species, formed at the early stage of aggregation remain, however, poorly understood and are hypothezised to be the most toxic aggregates. Here, we studied the formation of wild-type (WT) and mutant (A30P, A53T, and E46K) dimers of α-synuclein using coarse-grained molecular dynamics. We identified two principal segments of the sequence with a higher propensity to aggregate in the early stage of dimerization: residues 36-55 and residues 66-95. The transient α-helices (residues 53-65 and 73-82) of α-synuclein monomers are destabilized by A53T and E46K mutations, which favors the formation of fibril native contacts in the N-terminal region, whereas the helix 53-65 prevents the propagation of fibril native contacts along the sequence for the WT in the early stages of dimerization. The present results indicate that dimers do not adopt the Greek key motif of the monomer fold in fibrils but form a majority of disordered aggregates and a minority (9-15%) of pre-fibrillar dimers both with intra-molecular and intermolecular β-sheets. The percentage of residues in parallel β-sheets is by increasing order monomer α-synuclein aggregation step, the dimerization, is a complicated phenomenon that does not only involve the NAC region.

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