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Insights into structure, stability, and toxicity of monomeric and aggregated polyglutamine models from molecular dynamics simulations.

ABSTRACT: Nine genetically inherited neurodegenerative diseases are linked to abnormal expansions of a polyglutamine (polyQ) encoding region. Over the years, several structural models for polyQ regions have been proposed and confuted. The cross-beta-spine steric zipper motif, identified recently for the GNNQQNY peptide, represents an attractive model for amyloid fibers formed by polyQ fragments. Here we report a detailed molecular dynamics investigation of polyQ models assembled by cross-beta-spine steric zipper motifs. Our simulations indicate clearly that these assemblies are very stable. Glutamine side chains contribute strongly to the overall stability of the models by fitting perfectly within the zipper. In contrast to GNNQQNY zipper motifs, hydrogen bonding interactions provide a significant contribution to the overall stability of polyQ models. Molecular dynamics simulations carried out on monomeric polyQ forms (composed by 40-60 residues) show clearly that they can also assume structures stabilized by steric zipper motifs. Based on these findings, we build monomeric polyQ models that can explain recent data on the toxicity exerted by these species. In a more general context, our data suggests that polyQ models with interdigitated side chains can provide a structural rationale to several literature experiments on polyQ formation, stability, and toxicity.

SUBMITTER: Esposito L

PROVIDER: S-EPMC2367175 | biostudies-literature | 2008 May

REPOSITORIES: biostudies-literature

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Insights into structure, stability, and toxicity of monomeric and aggregated polyglutamine models from molecular dynamics simulations.

Esposito Luciana L Paladino Antonella A Pedone Carlo C Vitagliano Luigi L

Biophysical journal 20080130 10

Nine genetically inherited neurodegenerative diseases are linked to abnormal expansions of a polyglutamine (polyQ) encoding region. Over the years, several structural models for polyQ regions have been proposed and confuted. The cross-beta-spine steric zipper motif, identified recently for the GNNQQNY peptide, represents an attractive model for amyloid fibers formed by polyQ fragments. Here we report a detailed molecular dynamics investigation of polyQ models assembled by cross-beta-spine steric ...[more]

PMID: 18234827

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Project description:Deposition of insoluble amyloid plaques is frequently associated with a large variety of neurodegenerative diseases. However, data collected in the last decade have suggested that the neurotoxic action is exerted by prefibrillar, soluble assemblies of amyloid-forming proteins and peptides. The scarcity of structural data available for both amyloid-like fibrils and soluble oligomers is a major limitation for the definition of the molecular mechanisms linked to the onset of these diseases. Recently, the structural characterization of GNNQQNY and other peptides has shown a general feature of amyloid-like fibers, the so-called steric zipper motif. However, very little is known still about the prefibrillar oligomeric forms. By using replica exchange molecular dynamics we carried out extensive analyses of the properties of several small and medium GNNQQNY aggregates arranged through the steric zipper motif. Our data show that the assembly formed by two sheets, each made of two strands, arranged as in the crystalline states are highly unstable. Conformational free energy surfaces indicate that the instability of the model can be ascribed to the high reactivity of edge backbone hydrogen bonding donors/acceptors. On the other hand, data on larger models show that steric zipper interactions may keep small oligomeric forms in a stable state. These models simultaneously display two peculiar structural motifs: a tightly packed steric zipper interface and a large number of potentially reactive exposed strands. The presence of highly reactive groups on these assemblies likely generates two distinct evolutions. On one side the reactive groups quickly lead, through self-association, to the formation of ordered fibrils, on the other they may interfere with several cellular components thereby generating toxic effects. In this scenario, fiber formation propensity and toxicity of oligomeric states are two different manifestations of the same property: the hyper-reactivity of the exposed strands.

Dataset Information

Insights into structure, stability, and toxicity of monomeric and aggregated polyglutamine models from molecular dynamics simulations.

Publications

Insights into structure, stability, and toxicity of monomeric and aggregated polyglutamine models from molecular dynamics simulations.

Similar Datasets

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