Dataset Information

Unfolding of the amyloid ?-peptide central helix: mechanistic insights from molecular dynamics simulations.

ABSTRACT: Alzheimer's disease (AD) pathogenesis is associated with formation of amyloid fibrils caused by polymerization of the amyloid ?-peptide (A?), which is a process that requires unfolding of the native helical structure of A?. According to recent experimental studies, stabilization of the A? central helix is effective in preventing A? polymerization into toxic assemblies. To uncover the fundamental mechanism of unfolding of the A? central helix, we performed molecular dynamics simulations for wild-type (WT), V18A/F19A/F20A mutant (MA), and V18L/F19L/F20L mutant (ML) models of the A? central helix. It was quantitatively demonstrated that the stability of the ?-helical conformation of both MA and ML is higher than that of WT, indicating that the ?-helical propensity of the three nonpolar residues (18, 19, and 20) is the main factor for the stability of the whole A? central helix and that their hydrophobicity plays a secondary role. WT was found to completely unfold by a three-step mechanism: 1) loss of ?-helical backbone hydrogen bonds, 2) strong interactions between nonpolar sidechains, and 3) strong interactions between polar sidechains. WT did not completely unfold in cases when any of the three steps was omitted. MA and ML did not completely unfold mainly due to the lack of the first step. This suggests that disturbances in any of the three steps would be effective in inhibiting the unfolding of the A? central helix. Our findings would pave the way for design of new drugs to prevent or retard AD.

SUBMITTER: Ito M

PROVIDER: S-EPMC3049775 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Unfolding of the amyloid β-peptide central helix: mechanistic insights from molecular dynamics simulations.

Ito Mika M Johansson Jan J Strömberg Roger R Nilsson Lennart L

PloS one 20110307 3

Alzheimer's disease (AD) pathogenesis is associated with formation of amyloid fibrils caused by polymerization of the amyloid β-peptide (Aβ), which is a process that requires unfolding of the native helical structure of Aβ. According to recent experimental studies, stabilization of the Aβ central helix is effective in preventing Aβ polymerization into toxic assemblies. To uncover the fundamental mechanism of unfolding of the Aβ central helix, we performed molecular dynamics simulations for wild- ...[more]

PMID: 21408230

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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

Unfolding of the amyloid ?-peptide central helix: mechanistic insights from molecular dynamics simulations.

Publications

Unfolding of the amyloid β-peptide central helix: mechanistic insights from molecular dynamics simulations.

Similar Datasets

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