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Insight into α-synuclein plasticity and misfolding from differential micelle binding.

Misfolded species of the 140-residue protein α-synuclein (αS) are implicated in the demise of dopaminergic neurons, resulting in fatal neurodegeneration. The intrinsically unstructured protein binds curved synaptic vesicle membranes in helical conformations but misfolds into amyloid fibrils via β-sheet interactions. Breaks in helical αS conformation may offer a pathway to transition from helical to sheet conformation. Here, we explore the evolution of broken αS helix conformations formed in complex with SDS and SLAS micelles by molecular dynamics simulations. The population distribution of experimentally observed αS conformations is related to the spatial concentration of intrinsic micelle shape perturbations. For the success of micelle-induced αS folding, we posit the length of the first helical segment formed, which controls micelle ellipticity, to be a key determinant. The degree of micelle curvature relates to the arrangement and segmental motions of helical secondary structure elements. A criterion for assessing the reproduction of such intermediate time scale protein dynamics is introduced by comparing the sampling of experimental and simulated spin label distributions. Finally, at the sites of breaks in the elongated, marginally stable αS helix, vulnerability to forming a transient, intramolecular β-sheet is identified. Upon subsequent intermolecular β-sheet pairing, pathological αS amyloid formation from initial helical conformation is thus achievable.