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On the ubiquity of helical α-synuclein tetramers

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Show simple item record Xu, Liang Bhattacharya, Shanyon Thompson, Damien 2019-10-08T13:24:29Z 2019
dc.description peer-reviewed en_US
dc.description The full text of this article will not be available in ULIR until the embargo expires on the 22/95/2020
dc.description.abstract 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. en_US
dc.language.iso eng en_US
dc.publisher Royal Society of Chemistry en_US
dc.relation 15CDA3491 en_US
dc.relation.ispartofseries Physical Chemistry Chemical Physics;21, pp. 12036-12043
dc.rights © 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 en_US
dc.subject α-synuclein tetramers en_US
dc.subject helical tetramers en_US
dc.title On the ubiquity of helical α-synuclein tetramers en_US
dc.type info:eu-repo/semantics/article en_US
dc.type.supercollection all_ul_research en_US
dc.type.supercollection ul_published_reviewed en_US
dc.identifier.doi 10.1039/C9CP02464F
dc.contributor.sponsor SFI en_US
dc.contributor.sponsor HEA en_US
dc.relation.projectid 15/CDA/3491 en_US 2020-05-22
dc.embargo.terms 2020-05-22 en_US
dc.rights.accessrights info:eu-repo/semantics/embargoedAccess en_US

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