Effects of the Arctic (E22-->G) mutation on amyloid beta-protein folding: discrete molecular dynamics study

The 40-42 residue amyloid beta-protein (Abeta) plays a central role in the pathogenesis of Alzheimer's disease (AD). Of the two main alloforms, Abeta40 and Abeta42, the longer Abeta42 is linked particularly strongly to AD. Despite the relatively small two amino acid length difference in primary...

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Bibliographic Details
Published in:Journal of the American Chemical Society 2008-12, Vol.130 (51), p.17413-17422
Main Authors: Lam, A R, Teplow, D B, Stanley, H E, Urbanc, B
Format: Article
Language:English
Subjects:
Amyloid beta-Peptides - chemistry
Amyloid beta-Peptides - genetics
Animals
Circular Dichroism
Computer Simulation
Drug Design
Humans
Hydrogen Bonding
Models, Statistical
Mutation
Neurons - metabolism
Peptides - chemistry
Protein Conformation
Protein Folding
Protein Structure, Secondary
Protein Structure, Tertiary
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Summary:The 40-42 residue amyloid beta-protein (Abeta) plays a central role in the pathogenesis of Alzheimer's disease (AD). Of the two main alloforms, Abeta40 and Abeta42, the longer Abeta42 is linked particularly strongly to AD. Despite the relatively small two amino acid length difference in primary structure, in vitro studies demonstrate that Abeta40 and Abeta42 oligomerize through distinct pathways. Recently, a discrete molecular dynamics (DMD) approach combined with a four-bead protein model recapitulated the differences in Abeta40 and Abeta42 oligomerization and led to structural predictions amenable to in vitro testing. Here, the same DMD approach is applied to elucidate folding of Abeta40, Abeta42, and two mutants, [G22]Abeta40 and [G22]Abeta42, which cause a familial ("Arctic") form of AD. The implicit solvent in the DMD approach is modeled by amino acid-specific hydropathic and electrostatic interactions. The strengths of these effective interactions are chosen to best fit the temperature dependence of the average beta-strand content in Abeta42 monomer, as determined using circular dichroism (CD) spectroscopy. In agreement with these CD data, we show that at physiological temperatures, the average beta-strand content in both alloforms increases with temperature. Our results predict that the average beta-strand propensity should decrease in both alloforms at temperatures higher than approximately 370 K. At physiological temperatures, both Abeta40 and Abeta42 adopt a collapsed-coil conformation with several short beta-strands and a small (
ISSN:0002-7863
1520-5126
DOI:10.1021/ja804984h