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An atomic model for the pleated beta-sheet structure of abeta amyloid protofilaments.

Authors
Li-L; Darden-TA; Bartolotti-L; Kominos-D; Pedersen-LG
Source
Biophys J 1999 Jun; 76(6):2871-2878
NIOSHTIC No.
20025381
Abstract
Synchrotron x-ray studies on amyloid fibrils have suggested that the stacked pleated beta-sheets are twisted so that a repeating unit of 24 beta-strands forms a helical turn around the fibril axis (Sunde et al., J. Mol. Biol. 273:729-739). Based on this morphological study, we have constructed an atomic model for the twisted pleated beta-sheet of human Abeta amyloid protofilament. In the model, 48 monomers of Abeta 12-42 stack (four per layer) to form a helical turn of beta-sheet. Each monomer is in an antiparallel beta-sheet conformation with a turn located at residues 25-28. Residues 17-21 and 31-36 form a hydrophobic core along the fibril axis. The hydrophobic core should play a critical role in initializing Abeta aggregation and in stabilizing the aggregates. The model was tested using molecular dynamics simulations in explicit aqueous solution, with the particle mesh Ewald (PME) method employed to accommodate long-range electrostatic forces. Based on the molecular dynamics simulations, we hypothesize that an isolated protofilament, if it exists, may not be twisted, as it appears to be when in the fibril environment. The twisted nature of the protofilaments in amyloid fibrils is likely the result of stabilizing packing interactions of the protofilaments. The model also provides a binding mode for Congo red on Abeta amyloid fibrils. The model may be useful for the design of Abeta aggregation inhibitors.
Keywords
Models; X-ray-analysis; Simulation-methods; Physiological-factors; Environmental-factors
Contact
Dr. Lee G. Pedersen, Department of Chemistry, CB# 3290, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-3290
CODEN
BIOJAU
Publication Date
19990601
Document Type
Journal Article
Email Address
pedersen@niehs.nih.gov
Fiscal Year
1999
NTIS Accession No.
NTIS Price
Issue of Publication
6
ISSN
0006-3495
NIOSH Division
HELD
Source Name
Biophysical Journal
State
WV; NC; NJ
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