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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

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

Cruz L L Rao J Srinivasa JS Teplow D B DB Urbanc B B

The journal of physical chemistry. B 20120524 22

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 w ...[more]

PMID: 22587454

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Project description:In the more than a century since its identification, Alzheimer's disease has become the archetype of amyloid diseases. The first glimpses of the chemical basis of Alzheimer's disease began with the identification of "amyloid" plaques in the brain in 1892 and extended to the identification of proteinaceous fibrils with "cross-?" structure in 1968. Further efforts led to the discovery of the ?-amyloid peptide, A?, as a 40- or 42-amino acid peptide that is responsible for the plaques and fibrils. At this point, a three-decade-long marathon began to elucidate the structure of the fibrils and identify the molecular basis of Alzheimer's disease. Along the way, an alternative model began to emerge in which small aggregates of A?, called "oligomers", rather than fibrils, are the culprits that lead to neurodegeneration in Alzheimer's disease. This Account describes what is known about the structures of the fibrils and details our research group's efforts to understand the structural, biophysical, and biological properties of the oligomers in amyloid diseases. ?-Sheets are the building blocks of amyloid fibrils and oligomers. Amyloid fibrils generally consist of extended networks of parallel ?-sheets. Amyloid oligomers appear to be more compact enclosed structures, some of which are thought to be composed of antiparallel ?-sheets comprising ?-hairpins. ?-Hairpins are special because their twisted shape, hydrophobic surfaces, and exposed hydrogen-bonding edges impart a unique propensity to form compact assemblies. Our laboratory has developed macrocyclic ?-sheets that are designed to mimic ?-hairpins formed by amyloidogenic peptides and proteins. The ?-hairpin mimics contain two ?-strand peptide fragments linked together at their N- and C-termini by two ?-linked ornithine turn mimics to create a macrocycle. An N-methyl group is installed on one of the ?-strands to prevent uncontrolled aggregation. These design features facilitate crystallization of the ?-hairpin mimics and determination of the X-ray crystallographic structures of the oligomers that they form. During the past few years, our laboratory has elucidated the X-ray crystallographic structures of oligomers formed by ?-hairpin mimics derived from A?, ?-synuclein, and ?2-microglobulin. Out of these three amyloidogenic peptides and proteins, the A? ?-hairpin mimics have provided the most insight into amyloid oligomers. Our studies have revealed a previously undiscovered mode of self-assembly, whereby three A? ?-hairpin mimics assemble to form a triangular trimer. The triangular trimers are remarkable, because they contain two largely hydrophobic surfaces that pack together with other triangular trimers to form higher-order oligomers, such as hexamers and dodecamers. Some of the dodecamers pack in the crystal lattice to form annular porelike assemblies. Some of the ?-hairpin mimics and triangular trimers assemble in solution to form oligomers that recapitulate the crystallographically observed oligomers. These oligomers exhibit toxicity toward neuronally derived cells, recapitulating the toxicity of the oligomers formed by full-length amyloidogenic peptides and proteins. These findings are significant, because they address a gap in understanding the molecular basis of amyloid diseases. We anticipate that these studies will pave the way for developing diagnostics and therapeutics to combat Alzheimer's disease, Parkinson's disease, and other amyloid diseases.

Dataset Information

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

Publications

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

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