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  An atomistic view of amyloidogenic self-assembly: Structure and dynamics of heterogeneous conformational states in the pre-nucleation phase.

Matthes, D., Gapsys, V., Brennecke, J. T., & de Groot, B. L. (2016). An atomistic view of amyloidogenic self-assembly: Structure and dynamics of heterogeneous conformational states in the pre-nucleation phase. Scientific Reports, 6: 33156. doi:10.1038/srep33156.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002B-7B31-E Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002C-82F2-1
Genre: Journal Article

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Matthes, D.1, Author              
Gapsys, V.1, Author              
Brennecke, J. T.1, Author              
de Groot, B. L.1, Author              
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1Research Group of Computational Biomolecular Dynamics, MPI for biophysical chemistry, Max Planck Society, ou_578573              

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 Abstract: The formation of well-defined filamentous amyloid structures involves a polydisperse collection of oligomeric states for which relatively little is known in terms of structural organization. Here we use extensive, unbiased explicit solvent molecular dynamics (MD) simulations to investigate the structural and dynamical features of oligomeric aggregates formed by a number of highly amyloidogenic peptides at atomistic resolution on the mu s time scale. A consensus approach has been adopted to analyse the simulations in multiple force fields, yielding an in-depth characterization of pre-fibrillar oligomers and their global and local structure properties. A collision cross section analysis revealed structurally heterogeneous aggregate ensembles for the individual oligomeric states that lack a single defined quaternary structure during the pre-nucleation phase. To gain insight into the conformational space sampled in early aggregates, we probed their substructure and found emerging beta-sheet subunit layers and a multitude of ordered intermolecular beta-structure motifs with growing aggregate size. Among those, anti-parallel out-of-register beta-strands compatible with toxic beta-barrel oligomers were particularly prevalent already in smaller aggregates and formed prior to ordered fibrillar structure elements. Notably, also distinct fibril-like conformations emerged in the oligomeric state and underscore the notion that pre-nucleated oligomers serve as a critical intermediate step on-pathway to fibrils.

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Language(s): eng - English
 Dates: 2016-09-12
 Publication Status: Published online
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 Rev. Method: Peer
 Identifiers: DOI: 10.1038/srep33156
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Title: Scientific Reports
Source Genre: Journal
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Pages: 19 Volume / Issue: 6 Sequence Number: 33156 Start / End Page: - Identifier: -