Molecular dynamics simulation reveals that switchable combinations of β-sheets underlie the prion-like properties of α-synuclein amyloids.
Diversity of prion strains is one of the most mysterious traits of prions because they are mere aggregates of abnormally-folded forms of single protein species, prion protein (PrPSc), without genome. Although the strain-specific properties are hypothesized to be enciphered in the strain-specific structures of PrPSc instead of nucleotide genome, specifically what structure can code the information remains an enigma due to the incompatibility of PrPSc with structural analyses. Although the strain diversity was regarded as unique to prions, recently other disease-associated amyloids of -synuclein (Syn) or tau are also reported to have \"strains\". As detailed structures of Syn amyloid are already identified and the properties of mutant Syn associated with familial Parkinsons diseases, e.g. A53T, H50Q, and G51D, have been characterized, structure-phenotype relations of this type of amyloid could be investigated by using the Syn amyloid as a model. Here we intensively investigated the mutant Syn amyloids by molecular dynamics simulation to characterize influences of mutations on the structures of homo- or hetero-oligomer stacks of the amyloid. The simulations revealed directionality of the amyloid stack, remote effects of the mutations on distant {beta}-sheets, existence of at least two switchable interfaces/amyloid cores, and distinct effects of hetero-oligomerization depending on mutation types. Collectively, those findings implied a possible mechanism of the strain diversity of the amyloids which have multiple in-register parallel {beta}-sheets side-by-side, and support the view that their prion-like properties are inherent in the characteristic structures. We expect that the notion is also applicable to PrPSc.