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On the ubiquity of helical α-synuclein tetramers

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journal contribution
posted on 2019-10-08, 13:24 authored by Liang Xu, Shayon BhattacharyaShayon Bhattacharya, DAMIEN THOMPSONDAMIEN THOMPSON
The experimental finding that α-synuclein (αS) occurs physiologically as a helically folded tetramer begs the question: why are helical tetramers the most populated multimers? While the helical tetramer is known to resist aggregation, the assembly mechanism of αS peptides remains largely unknown. By rationally designing a series of helical multimers from dimer to octamer, we characterized the free energy landscape of wild-type and mutated multimers using molecular dynamics computer simulations. Competition between supramolecular packing and solvation results in well-hydrated dimers and trimers, and more screened pentamers to octamers, with the helical tetramer possessing the most balanced structure with the lowest activation energy. Our data suggest that familial mutants are very sensitive to alterations in monomer packing that would in turn raise the energy barriers for multimerization. Finally, the hypothesis that the αS tetramer forms a soluble, benign “dead end” to circumvent aggregation is supported by its computed very weak association with negatively charged cell membranes.

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Publication

Physical Chemistry Chemical Physics;21, pp. 12036-12043

Publisher

Royal Society of Chemistry

Note

peer-reviewed

Other Funding information

SFI, HEA

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© 2019 Royal Society of Chemistry. Personal use of this material is permitted. Permission from Royal Society of Chemistry must be obtained for all other uses, in any current or future media, including reprinting/republishing this material for advertising or promotional purposes, creating new collective works, for resale or redistribution to servers or lists, or reuse of any copyrighted component of this work in other works

Language

English

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