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  Driving forces and structural determinants of steric zipper peptide oligomer formation elucidated by atomistic simulations.

Matthes, D., Gapsys, V., & de Groot, B. L. (2012). Driving forces and structural determinants of steric zipper peptide oligomer formation elucidated by atomistic simulations. Journal of Molecular Biology, 421(2-3), 390-416. doi:10.1016/j.jmb.2012.02.004.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-000F-9C53-B Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0027-CAB3-4
Genre: Journal Article

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Matthes, D.1, Author              
Gapsys, V.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: Understanding the structural and energetic requirements of non-fibrillar oligomer formation harbors the potential to decipher an important yet still elusive part of amyloidogenic peptide and protein aggregation. Low-molecular-weight oligomers are described to be transient and polymorphic intermediates in the nucleated self-assembly process to highly ordered amyloid fibers and were additionally found to exhibit a profound cytotoxicity. However, detailed structural information on the oligomeric species involved in the nucleation cannot be readily inferred from experiments. Here, we study the spontaneous assembly of steric zipper peptides from the tau protein, insulin and α-synuclein with atomistic molecular dynamics simulations on the microsecond timescale. Detailed analysis of the forces driving the oligomerization reveals a common two-step process akin to a general condensation-ordering mechanism and thus provides a rational understanding of the molecular basis of peptide self-assembly. Our results suggest that the initial formation of partially ordered peptide oligomers is governed by the solvation free energy, whereas the dynamical ordering and emergence of β-sheets are mainly driven by optimized inter-peptide interactions in the collapsed state. A novel mapping technique based on collective coordinates is employed to highlight similarities and differences in the conformational ensemble of small oligomer structures. Elucidating the dynamical and polymorphic β-sheet oligomer conformations at atomistic detail furthermore suggests complementary sheet packing characteristics similar to steric zipper structures, but with a larger heterogeneity in the strand alignment pattern and sheet-to-sheet arrangements compared to the cross-β motif found in the fibrillar or crystalline states.

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Language(s): eng - English
 Dates: 2012-02-082012-08-10
 Publication Status: Published in print
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 Rev. Method: Peer
 Identifiers: DOI: 10.1016/j.jmb.2012.02.004
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Title: Journal of Molecular Biology
Source Genre: Journal
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Pages: 27 Volume / Issue: 421 (2-3) Sequence Number: - Start / End Page: 390 - 416 Identifier: -