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Issue 2, 2011
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Clarifying the influence of core amino acid hydrophobicity, secondary structure propensity, and molecular volume on amyloid-β 16–22 self-assembly

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Abstract

The self-assembly of amyloid peptides is influenced by hydrophobicity, charge, secondary structure propensity, and sterics. Previous experiments have shown that increasing hydrophobicity at the aromatic positions of the amyloid-β 16–22 fragment (Aβ(16–22)) without introducing steric restraints greatly increases the rate of self-assembly and thermodynamically stabilizes the resulting fibrils [Senguen et al., Mol. BioSyst., 2011, DOI: 10.1039/c0mb00080a]. Conversely, when increasing side chain hydrophobicity coincides with an increase in side chain volume, the increase in the rate of self-assembly is offset by a thermodynamic destabilization of the resulting amyloid fibrils when direct cross-strand side chain interactions occur. These findings indicate that steric effects also influence the self-assembly of amyloidogenic peptides. Herein, the aromatic Phe residues at positions 19, 20, and 19,20 of Aβ(16–22) have been systematically replaced by Val, Leu, Ile, or hexafluoroleucine (Hfl) and amyloid formation has been characterized. The Val variants, despite the high β-sheet propensity of Val, were thermodynamically destabilized (ΔΔG = +0.1–0.4 kcal mol−1) relative to the wild-type with the double mutant failing to self-assemble at the concentrations studied. Conversely, the Leu and Ile variants formed fibrils at enhanced rates relative to wild-type and exhibited similar, or in some cases enhanced thermodynamic stabilities relative to the wild-type (ΔΔG = 0−0.6 kcal mol−1). The more hydrophobic Hfl variants were greatly stabilized (ΔΔG = −0.3−2.1 kcal mol−1) relative to the wild-type. These data indicate that hydrophobicity and steric effects both influence peptide self-assembly processes, including nucleation and fibrillization rates and the thermodynamic stability of the resulting fibrils.

Graphical abstract: Clarifying the influence of core amino acid hydrophobicity, secondary structure propensity, and molecular volume on amyloid-β 16–22 self-assembly

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Supplementary files

Article information


Submitted
27 Sep 2010
Accepted
10 Nov 2010
First published
07 Dec 2010

Mol. BioSyst., 2011,7, 497-510
Article type
Paper

Clarifying the influence of core amino acid hydrophobicity, secondary structure propensity, and molecular volume on amyloid-β 16–22 self-assembly

F. T. Senguen, T. M. Doran, E. A. Anderson and B. L. Nilsson, Mol. BioSyst., 2011, 7, 497
DOI: 10.1039/C0MB00210K

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