Alpha-synuclein phosphorylation induces amyloid conversion via enhanced electrostatic bridging: Insights from molecular modeling of the full-length protein.

Fibril formation from alpha-synuclein is a key point in Parkinson's disease, multiple system atrophy, and other synucleinopathies. The mechanism of the amyloid-like conversion followed by the formation of pre-fibrillar soluble oligomers and fibrils is not completely clear; furthermore, it is unclear how the Parkinson's disease-related point mutations located in the pre-NAC region enhance fibrillation. In the present paper, atomistic replica exchange molecular dynamics simulations of the full-length alpha-synuclein and its two mutants, A53T and E46K, elucidated amyloid conversion intermediates. Both mutants demonstrated an enhanced tendency for the conversion but in different manners; the main intermediate conformations populated in the WT alpha-synuclein conformational ensemble disappeared due to mutations, indicating a different conversion pathway. Analysis of the preferable beta-hairpin positions and intermediate conformations seems to reflect a tendency to form a particular amyloid fibril polymorph. A strong elevation of amyloid transformation level was shown also for Ser129-phosphorylated alpha-synuclein. Altered intermediate conformations, the most preferable beta-hairpin positions in the NAC region, and prevalent salt bridges propose the formation of so-called polymorph 2 or even a novel type of fibrils. A better understanding of the detailed mechanism of the amyloid conversion sheds light on the effect of Lewy body-related phosphorylation and might help in the development of new therapeutics for synucleinopathies.