Dataset Information

Spontaneous formation of twisted A?(16-22) fibrils in large-scale molecular-dynamics simulations.

ABSTRACT: Protein aggregation is associated with fatal neurodegenerative diseases, including Alzheimer's and Parkinson's. Mapping out kinetics along the aggregation pathway could provide valuable insights into the mechanisms that drive oligomerization and fibrillization, but that is beyond the current scope of computational research. Here we trace out the full kinetics of the spontaneous formation of fibrils by 48 A?(16-22) peptides, following the trajectories in molecular detail from an initial random configuration to a final configuration of twisted protofilaments with cross-?-structure. We accomplish this by performing large-scale molecular-dynamics simulations based on an implicit-solvent, intermediate-resolution protein model, PRIME20. Structural details such as the intersheet distance, perfectly antiparallel ?-strands, and interdigitating side chains analogous to a steric zipper interface are explained by and in agreement with experiment. Two characteristic fibrillization mechanisms - nucleation/templated growth and oligomeric merging/structural rearrangement - emerge depending on the temperature.

SUBMITTER: Cheon M

PROVIDER: S-EPMC3218340 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Spontaneous formation of twisted Aβ(16-22) fibrils in large-scale molecular-dynamics simulations.

Cheon Mookyung M Chang Iksoo I Hall Carol K CK

Biophysical journal 20111115 10

Protein aggregation is associated with fatal neurodegenerative diseases, including Alzheimer's and Parkinson's. Mapping out kinetics along the aggregation pathway could provide valuable insights into the mechanisms that drive oligomerization and fibrillization, but that is beyond the current scope of computational research. Here we trace out the full kinetics of the spontaneous formation of fibrils by 48 Aβ(16-22) peptides, following the trajectories in molecular detail from an initial random co ...[more]

PMID: 22098748

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Project description:The aggregation of amyloid-? (A?) peptides into senile plaques is a hallmark of Alzheimer's disease (AD) and is hypothesized to be the primary cause of AD related neurodegeneration. Previous studies have shown the ability of curcumin to both inhibit the aggregation of A? peptides into oligomers or fibrils and reduce amyloids in vivo. Despite the promise of curcumin and its derivatives to serve as diagnostic, preventative, and potentially therapeutic AD molecules, the mechanism by which curcumin and its derivatives bind to and inhibit A? fibrils' formation remains elusive. Here, we investigated curcumin and a set of curcumin derivatives in complex with a hexamer peptide model of the A?1-42 fibril using nearly exhaustive docking, followed by multi-ns molecular dynamics simulations, to provide atomistic-detail insights into the molecules' binding and inhibitory properties. In the vast majority of the simulations, curcumin and its derivatives remain firmly bound in complex with the fibril through primarily three different principle binding modes, in which the molecules interact with residue domain 17LVFFA21, in line with previous experiments. In a small subset of these simulations, the molecules partly dissociate the outermost peptide of the A?1-42 fibril by disrupting ?-sheets within the residue domain 12VHHQKLVFF20. A comparison between binding modes leading or not leading to partial dissociation of the outermost peptide suggests that the latter is attributed to a few subtle key structural and energetic interaction-based differences. Interestingly, partial dissociation appears to be either an outcome of high affinity interactions or a cause leading to high affinity interactions between the molecules and the fibril, which could partly serve as a compensation for the energy loss in the fibril due to partial dissociation. In conjunction with this, we suggest a potential inhibition mechanism of ??1-42 aggregation by the molecules, where the partially dissociated 16KLVFF20 domain of the outermost peptide could either remain unstructured or wrap around to form intramolecular interactions with the same peptide's 29GAIIG33 domain, while the molecules could additionally act as a patch against the external edge of the second outermost peptide's 16KLVFF20 domain. Thereby, individually or concurrently, these could prohibit fibril elongation.

Dataset Information

Spontaneous formation of twisted A?(16-22) fibrils in large-scale molecular-dynamics simulations.

Publications

Spontaneous formation of twisted Aβ(16-22) fibrils in large-scale molecular-dynamics simulations.

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