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D-Amino Acid Pseudopeptides as Potential Amyloid-Beta Aggregation Inhibitors.

ABSTRACT: A causative factor for neurotoxicity associated with Alzheimer's disease is the aggregation of the amyloid-β (Aβ) peptide into soluble oligomers. Two all d-amino acid pseudo-peptides, SGB1 and SGD1, were designed to stop the aggregation. Molecular dynamics (MD) simulations have been carried out to study the interaction of the pseudo-peptides with both Aβ13⁻23 (the core recognition site of Aβ) and full-length Aβ1⁻42. Umbrella sampling MD calculations have been used to estimate the free energy of binding, ∆G, of these peptides to Aβ13⁻23. The highest ∆Gbinding is found for SGB1. Each of the pseudo-peptides was also docked to Aβ1⁻42 and subjected up to seven microseconds of all atom molecular dynamics simulations. The resulting structures lend insight into how the dynamics of Aβ1⁻42 are altered by complexation with the pseudo-peptides and confirmed that SGB1 may be a better candidate for developing into a drug to prevent Alzheimer's disease.

SUBMITTER: Mehrazma B

PROVIDER: S-EPMC6225248 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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d-Amino Acid Pseudopeptides as Potential Amyloid-Beta Aggregation Inhibitors.

Mehrazma Banafsheh B Opare Stanley S Petoyan Anahit A Rauk Arvi A

Molecules (Basel, Switzerland) 20180918 9

A causative factor for neurotoxicity associated with Alzheimer's disease is the aggregation of the amyloid-β (Aβ) peptide into soluble oligomers. Two all d-amino acid pseudo-peptides, SGB1 and SGD1, were designed to stop the aggregation. Molecular dynamics (MD) simulations have been carried out to study the interaction of the pseudo-peptides with both Aβ<sub>13⁻23</sub> (the core recognition site of Aβ) and full-length Aβ<sub>1⁻42</sub>. Umbrella sampling MD calculations have been used to estima ...[more]

PMID: 30231520

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Project description:Aging is the most important risk factor for neurodegenerative diseases associated with pathological protein aggregation such as Alzheimer's disease. Although aging is an important player, it remains unknown which molecular changes are relevant for disease initiation. Recently, it has become apparent that widespread protein aggregation is a common feature of aging. Indeed, several studies demonstrate that 100s of proteins become highly insoluble with age, in the absence of obvious disease processes. Yet it remains unclear how these misfolded proteins aggregating with age affect neurodegenerative diseases. Importantly, several of these aggregation-prone proteins are found as minor components in disease-associated hallmark aggregates such as amyloid-β plaques or neurofibrillary tangles. This co-localization raises the possibility that age-dependent protein aggregation directly contributes to pathological aggregation. Here, we show for the first time that highly insoluble proteins from aged Caenorhabditis elegans or aged mouse brains, but not from young individuals, can initiate amyloid-β aggregation in vitro. We tested the seeding potential at four different ages across the adult lifespan of C. elegans. Significantly, protein aggregates formed during the early stages of aging did not act as seeds for amyloid-β aggregation. Instead, we found that changes in protein aggregation occurring during middle-age initiated amyloid-β aggregation. Mass spectrometry analysis revealed several late-aggregating proteins that were previously identified as minor components of amyloid-β plaques and neurofibrillary tangles such as 14-3-3, Ubiquitin-like modifier-activating enzyme 1 and Lamin A/C, highlighting these as strong candidates for cross-seeding. Overall, we demonstrate that widespread protein misfolding and aggregation with age could be critical for the initiation of pathogenesis, and thus should be targeted by therapeutic strategies to alleviate neurodegenerative diseases.

Dataset Information

D-Amino Acid Pseudopeptides as Potential Amyloid-Beta Aggregation Inhibitors.

Publications

d-Amino Acid Pseudopeptides as Potential Amyloid-Beta Aggregation Inhibitors.

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