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000858896 1001_ $$00000-0002-5935-3332$$aIlie, Ioana M.$$b0$$eCorresponding author
000858896 245__ $$aIntrinsic Conformational Preferences and Interactions in α-Synuclein Fibrils: Insights from Molecular Dynamics Simulations
000858896 260__ $$aWashington, DC$$c2018
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000858896 520__ $$aAmyloid 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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000858896 7001_ $$0P:(DE-HGF)0$$aNayar, Divya$$b1
000858896 7001_ $$0P:(DE-HGF)0$$aden Otter, Wouter K.$$b2
000858896 7001_ $$00000-0003-2880-6383$$avan der Vegt, Nico F. A.$$b3$$eCorresponding author
000858896 7001_ $$0P:(DE-Juel1)159317$$aBriels, Willem$$b4$$eCorresponding author$$ufzj
000858896 773__ $$0PERI:(DE-600)2166976-4$$a10.1021/acs.jctc.8b00183$$gVol. 14, no. 6, p. 3298 - 3310$$n6$$p3298 - 3310$$tJournal of chemical theory and computation$$v14$$x1549-9626$$y2018
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