title: Dynamics of metastable β-hairpin structures in the folding nucleus of amyloid β-protein.
abstract: The amyloid β-protein (Aβ), which is present predominately as a 40- or 42-residue peptide, is postulated to play a seminal role in the pathogenesis of Alzheimer's disease (AD). Folding of the Aβ(21-30) decapeptide region is a critical step in the aggregation of Aβ. We report results of constant temperature all-atom molecular dynamics simulations in explicit water of the dynamics of monomeric Aβ(21-30) and its Dutch [Glu22Gln], Arctic [Glu22Gly], and Iowa [Asp23Asn] isoforms that are associated with familial forms of cerebral amyloid angiopathy and AD. The simulations revealed a variety of loop conformers that exhibited a hydrogen bond network involving the Asp23 and Ser26 amino acids. A population of conformers, not part of the loop population, was found to form metastable β-hairpin structures with the highest probability in the Iowa mutant. At least three β-hairpin structures were found that differed in their hydrogen bonding register, average number of backbone hydrogen bonds, and lifetimes. Analysis revealed that the Dutch mutant had the longest β-hairpin lifetime (≥500 ns), closely followed by the Iowa mutant (≈500 ns). Aβ(21-30) and the Arctic mutant had significantly lower lifetimes (≈200 ns). Hydrophobic packing of side chains was responsible for enhanced β-hairpin lifetimes in the Dutch and Iowa mutants, whereas lifetimes in Aβ(21-30) and its Arctic mutant were influenced by the backbone hydrogen bonding. The data suggest that prolonged β-hairpin lifetimes may impact peptide pathogenicity in vivo.
authors.affiliation: Department of Physics, 3141 Chestnut Street, Drexel University, Philadelphia, Pennsylvania 19104, United States. ccruz@drexel.edu
authors.forename: L
authors.initials: L
authors.lastname: Cruz
authors.forename: J Srinivasa
authors.initials: JS
authors.lastname: Rao
authors.forename: D B
authors.initials: DB
authors.lastname: Teplow
authors.forename: B
authors.initials: B
authors.lastname: Urbanc
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D017510:Protein Folding
chemical_list: D016229:Amyloid beta-Peptides