title: Solvent and mutation effects on the nucleation of amyloid beta-protein folding.
abstract: Experimental evidence suggests that the folding and aggregation of the amyloid beta-protein (Abeta) into oligomers is a key pathogenetic event in Alzheimer's disease. Inhibiting the pathologic folding and oligomerization of Abeta could be effective in the prevention and treatment of Alzheimer's disease. Here, using all-atom molecular dynamics simulations in explicit solvent, we probe the initial stages of folding of a decapeptide segment of Abeta, Abeta(21-30), shown experimentally to nucleate the folding process. In addition, we examine the folding of a homologous decapeptide containing an amino acid substitution linked to hereditary cerebral hemorrhage with amyloidosis-Dutch type, [Gln-22]Abeta(21-30). We find that: (i) when the decapeptide is in water, hydrophobic interactions and transient salt bridges between Lys-28 and either Glu-22 or Asp-23 are important in the formation of a loop in the Val-24-Lys-28 region of the wild-type decapeptide; (ii) in the presence of salt ions, salt bridges play a more prominent role in the stabilization of the loop; (iii) in water with a reduced density, the decapeptide forms a helix, indicating the sensitivity of folding to different aqueous environments; and (iv) the "Dutch" peptide in water, in contrast to the wild-type peptide, fails to form a long-lived Val-24-Lys-28 loop, suggesting that loop stability is a critical factor in determining whether Abeta folds into pathologic structures.
authors.affiliation: Center for Polymer Studies and Department of Physics, Boston University, Boston, MA 02215, USA. ccruz@bu.edu
authors.forename: Luis
authors.initials: L
authors.lastname: Cruz
authors.forename: Brigita
authors.initials: B
authors.lastname: Urbanc
authors.forename: Jose M
authors.initials: JM
authors.lastname: Borreguero
authors.forename: Noel D
authors.initials: ND
authors.lastname: Lazo
authors.forename: David B
authors.initials: DB
authors.lastname: Teplow
authors.forename: H Eugene
authors.initials: HE
authors.lastname: Stanley
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D057927:Hydrophobic and Hydrophilic Interactions; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D017510:Protein Folding; D017433:Protein Structure, Secondary; D012997:Solvents / Q000494:pharmacology*; D055672:Static Electricity; D014633:Valine / Q000235:genetics / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D012997:Solvents; D014633:Valine; D008239:Lysine