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Disorder at the Tips of a Disease-Relevant Aβ42 Amyloid Fibril: A Molecular Dynamics Study


Ilie, Ioana M; Caflisch, Amedeo (2018). Disorder at the Tips of a Disease-Relevant Aβ42 Amyloid Fibril: A Molecular Dynamics Study. Journal of Physical Chemistry B, 122:11072-11082.

Abstract

We present a simulation study of the early events of peptide dissociation from a fibril of the Alzheimer's Aβ42 peptide. The fibril consists of layers of two adjacent Aβ42 peptides each folded in an S-shaped structure which has been determined by solid state NMR spectroscopy of a monomorphic disease-relevant species. Multiple molecular dynamics runs (16 at 310 K and 15 at 370 K) were carried out starting from an 18-peptide protofibril for a cumulative sampling of about 15 μs. The simulations show structural stability of the fibrillar core and an overall increase in the twist to about 3 degrees. The N-terminal segment 1-14 is disordered in all peptides. At both ends of the fibril, the central segment 21-29, which includes part of the β strand, dissociates in some of the simulations. The β and β strands, residues 15-20 and 35-41, respectively, are structurally stable. The transient binding of the N-terminal stretch to the β strand of the adjacent peptide at the tip is likely to contribute to the arrest phase of the stop-and-go mechanism.

Abstract

We present a simulation study of the early events of peptide dissociation from a fibril of the Alzheimer's Aβ42 peptide. The fibril consists of layers of two adjacent Aβ42 peptides each folded in an S-shaped structure which has been determined by solid state NMR spectroscopy of a monomorphic disease-relevant species. Multiple molecular dynamics runs (16 at 310 K and 15 at 370 K) were carried out starting from an 18-peptide protofibril for a cumulative sampling of about 15 μs. The simulations show structural stability of the fibrillar core and an overall increase in the twist to about 3 degrees. The N-terminal segment 1-14 is disordered in all peptides. At both ends of the fibril, the central segment 21-29, which includes part of the β strand, dissociates in some of the simulations. The β and β strands, residues 15-20 and 35-41, respectively, are structurally stable. The transient binding of the N-terminal stretch to the β strand of the adjacent peptide at the tip is likely to contribute to the arrest phase of the stop-and-go mechanism.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Department of Biochemistry
07 Faculty of Science > Department of Biochemistry
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:17 July 2018
Deposited On:08 Mar 2019 12:54
Last Modified:25 Sep 2019 00:28
Publisher:American Chemical Society (ACS)
ISSN:1520-5207
OA Status:Closed
Publisher DOI:https://doi.org/10.1021/acs.jpcb.8b05236
PubMed ID:29965774

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