Dynamics of metastable ?-hairpin structures in the folding nucleus of amyloid ?-protein.

ABSTRACT: The amyloid ?-protein (A?), 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 A?(21-30) decapeptide region is a critical step in the aggregation of A?. We report results of constant temperature all-atom molecular dynamics simulations in explicit water of the dynamics of monomeric A?(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 ?-hairpin structures with the highest probability in the Iowa mutant. At least three ?-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 ?-hairpin lifetime (?500 ns), closely followed by the Iowa mutant (?500 ns). A?(21-30) and the Arctic mutant had significantly lower lifetimes (?200 ns). Hydrophobic packing of side chains was responsible for enhanced ?-hairpin lifetimes in the Dutch and Iowa mutants, whereas lifetimes in A?(21-30) and its Arctic mutant were influenced by the backbone hydrogen bonding. The data suggest that prolonged ?-hairpin lifetimes may impact peptide pathogenicity in vivo.

SUBMITTER: Cruz L 

PROVIDER: S-EPMC3394227 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature