Journal Article

FZJ-2018-07732

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Intrinsic Conformational Preferences and Interactions in α-Synuclein Fibrils: Insights from Molecular Dynamics Simulations

Ilie, I. M. (Corresponding author) ; Nayar, D. ; den Otter, W. K. ; van der Vegt, N. F. A. (Corresponding author) ; Briels, W. (Corresponding author)FZJ*

2018
Washington, DC

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Please use a persistent id in citations: doi:10.1021/acs.jctc.8b00183

Abstract: Amyloid formation by the intrinsically disordered α-synuclein protein is the hallmark of Parkinson’s disease. We present atomistic Molecular Dynamics simulations of the core of α-synuclein using enhanced sampling techniques to describe the conformational and binding free energy landscapes of fragments implicated in fibril stabilization. The theoretical framework is derived to combine the free energy profiles of the fragments into the reaction free energy of a protein binding to a fibril. Our study shows that individual fragments in solution have a propensity toward attaining non-β conformations, indicating that in a fibril β-strands are stabilized by interactions with other strands. We show that most dimers of hydrogen-bonded fragments are unstable in solution, while hydrogen bonding stabilizes the collective binding of five fragments to the end of a fibril. Hydrophobic effects make further contributions to the stability of fibrils. This study is the first of its kind where structural and binding preferences of the five major fragments of the hydrophobic core of α-synuclein have been investigated. This approach improves sampling of intrinsically disordered proteins, provides information on the binding mechanism between the core sequences of α-synuclein, and enables the parametrization of coarse grained models.

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Contributing Institute(s):

1. Weiche Materie (ICS-3)

Research Program(s):

1. 551 - Functional Macromolecules and Complexes (POF3-551) (POF3-551)

Appears in the scientific report 2018

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Database coverage:
; Clarivate Analytics Master Journal List ; Current Contents - Physical, Chemical and Earth Sciences ; IF >= 5 ; JCR ; NCBI Molecular Biology Database ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Web of Science Core Collection

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