One of the pathological hallmarks of Parkinson's disease is the formation of abnormal proteinaceous inclusions called Lewy bodies, which are intracellular aggregates primarily composed of the protein α-synuclein (α-syn). Within neurons, α-syn is mostly cytosolic and has been shown to be highly unstructured in its unbound state (soluble in its native form) both in vitro and in vivo. However, upon membrane association, it is well established that α-syn adopts an α-helical structure. The balance between the unstructured state and the α-helical conformation has been found to play an essential role in both the proposed physiological function of α-syn and its pathogenic aggregation. Our research group has employed molecular dynamics simulation and enhanced sampling methods to study the interaction between α-syn and cellular membrane. The composition of lipid molecules in our research mimics the lipid composition of synaptic vesicles. The simulations demonstrate that the lipids with charged head groups (phosphatidylserine, PS) play an essential role in the initial signaling between α-syn and the vesicle, even though their composition can be as low as 5%. Even though the folding of α-syn could not be observed for the timescale of the simulation, with enhanced sampling methods, the free energy profile of the folding of α-syn has supported that the presence of the outer leaflet of a synaptic vesicle significantly stabilized the helical structure. Further, we investigated the impact of the heterogeneity of lipid bilayer on its ability to facilitate the folding of α-syn.

Molecular dynamics study of the binding between synaptic vesicle and alpha-synuclein

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.