Amyloid beta(1–42) in aqueous environments: Effects of ionic strength and E22Q (Dutch) mutation

• Published in: Biochimica et biophysica acta 2013-12, Vol.1834 (12), p.2486-2493
• Main Authors: Bossis, Fabrizio, Palese, Luigi L.
• Format: Article
• Language: English
• Subjects: Alzheimer disease; Alzheimer's disease; Amino Acid Substitution; amyloid; Amyloid beta-Peptides - chemistry; Amyloid beta-Peptides - genetics; Amyloid-beta; Amyloidogenesis; aqueous solutions; Dutch mutation; electrostatic interactions; Humans; Hydrophobic and Hydrophilic Interactions; hydrophobicity; ionic strength; Misfolding; Molecular dynamics; Molecular Dynamics Simulation; mutants; mutation; Mutation, Missense; Osmolar Concentration; Peptide Fragments - chemistry; Peptide Fragments - genetics; peptides; Protein Folding; Protein Structure, Secondary; Solubility
• ISSN: 1570-9639; 0006-3002; 1878-1454
• DOI: 10.1016/j.bbapap.2013.08.010

Development of extracellular plaques characteristic of Alzheimer's disease is related to aggregation of amyloid peptides. The Aβ-42 peptide is the most aggregation prone species, and some missense mutant forms increase this aggregation ability. Due to its poor solubility as monomer in aqueous solutions, Aβ-42 conformational transitions in water have been largely investigated by molecular dynamics. Here we report an all-atom molecular dynamics analysis of the Aβ-42 peptide in aqueous environment using as starting conformation a structure obtained in an isotropic, low-polarity medium, representing a plausible model for the membrane-bound species. While previous studies commonly show that Aβ-42 is largely unstructured in aqueous solution, here we report that this peptide can adopt partially folded structures. Importance of ionic strength has been also investigated, showing that at physiological ionic strength condition a loop stabilizing electrostatic interaction involving Lys28 builds up. In addition, besides stable α-helix structures, we observe the appearance of 310 helix, similar to what was reported experimentally for the Aβ-40 species. The effect of E22Q (Dutch) mutation in high ionic strength condition has been explored. We show that this mutation has a dramatic impact on the Aβ-42 structure. Instead of a partially folded, but extended, conformation obtained with the wild type, the E22Q assumes a two-helix collapsed one due to the clustering of hydrophobic residues. Amyloid β-42 at 310K and physiological ionic strength: most populated structures of wild type and E22Q mutant peptides. [Display omitted] •Alzheimer's disease is related to aggregation of amyloid peptides.•The Aβ-42 peptide is the most aggregation prone species.•The E22Q (Dutch) mutation increases its toxicity.•We show that wild type Aβ-42 maintains a folded and extended structure.•E22Q mutant instead rapidly underwent hydrophobic collapse.