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Structure modeling and dynamics driven mutation and phosphorylation analysis of Beta-amyloid peptides.

ABSTRACT: The most common characteristics of diverse age-related neurodegenerative diseases are aggregation and accumulation of the misfolded protein in the brain. Alzheimer?s disease (AD) is one of these protein conformational diseases. Extracellular accumulation of amyloid ? (A?) is one the neuropathological hallmarks of Alzheimer disease. Various studies have shown that mutation in specific hydrophobic region of A? protein inhibit the formation of ? sheet, thus aggregation of this protein is stalled. The identification of such mutation in A? protein can help us in elucidating the etiology of sporadic A?. In our study we have selected three positions: 19ILU, 21ALA and 41ILU in A? protein based on their hydrophobic nature and substituted them with PRO ( ?Sheet breaker). The effects of the substitutions were analysed using molecular dynamics simulation studies. The results validated that the mutations in the specified regions change the hydrophobicity of the protein and the ?sheet formation was declined to zero per cent.

SUBMITTER: Singh SK

PROVIDER: S-EPMC4209365 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Structure modeling and dynamics driven mutation and phosphorylation analysis of Beta-amyloid peptides.

Singh Sunil Kumar SK Singh Ankita A Prakash Ved V C Selvaa Kumar SK

Bioinformation 20140930 9

The most common characteristics of diverse age-related neurodegenerative diseases are aggregation and accumulation of the misfolded protein in the brain. Alzheimer׳s disease (AD) is one of these protein conformational diseases. Extracellular accumulation of amyloid β (Aβ) is one the neuropathological hallmarks of Alzheimer disease. Various studies have shown that mutation in specific hydrophobic region of Aβ protein inhibit the formation of β sheet, thus aggregation of this protein is stalled. T ...[more]

PMID: 25352724

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Project description:Despite their unique advantages, the full potential of molecular probes for fluorescent monitoring of amyloid-β (Aβ) aggregates has not been fully exploited. This limited utility stems from the lack of knowledge about the hydrophobic interactions between the molecules of Aβ probes, as well as those between the probe and the Aβ aggregate. Herein, we report the first mechanistic study, which firmly establishes a structure-signaling relationship of fluorescent Aβ probes. We synthesized a series of five fluorescent Aβ probes based on an archetypal donor-acceptor-donor scaffold (denoted as SN1-SN5). The arylamino donor moieties were systematically varied to identify molecular factors that could influence the interactions between molecules of each probe and that could influence their fluorescence outcomes in conditions mimicking the biological milieu. Our probes displayed different responses to aggregates of Aβ, Aβ40 and Aβ42, two major isoforms found in Alzheimer's disease: SN2, having pyrrolidine donors, showed noticeable ratiometric fluorescence responses (Δν = 797 cm-1) to the Aβ40 and Aβ42 samples that contained oligomeric species, whereas SN4, having N-methylpiperazine donors, produced significant fluorescence turn-on signaling in response to Aβ aggregates, including oligomers, protofibrils, and fibrils (with turn-on ratios of 14 and 10 for Aβ42 and Aβ40, respectively). Mechanistic investigations were carried out by performing field-emission scanning electron microscopy, X-ray crystallography, UV-vis absorption spectroscopy, and steady-state and transient photoluminescence spectroscopy experiments. The studies revealed that the SN probes underwent preassembly prior to interacting with the Aβ species and that the preassembled structures depended profoundly on the subtle differences between the amino moieties of the different probes. Importantly, the studies demonstrated that the mode of fluorescence signaling (i.e., ratiometric response versus turn-on response) was primarily governed by stacking geometries within the probe preassemblies. Specifically, ratiometric fluorescence responses were observed for probes capable of forming J-assembly, whereas fluorescence turn-on responses were obtained for probes incapable of forming J-aggregates. This finding provides an important guideline to follow in future efforts at developing fluorescent probes for Aβ aggregation. We also conclude, on the basis of our study, that the rational design of such fluorescent probes should consider interactions between the probe molecules, as well as those between Aβ peptides and the probe molecule.

Dataset Information

Structure modeling and dynamics driven mutation and phosphorylation analysis of Beta-amyloid peptides.

Publications

Structure modeling and dynamics driven mutation and phosphorylation analysis of Beta-amyloid peptides.

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