Dataset Information

Molecular interactions between monoclonal oligomer-specific antibody 5E3 and its amyloid beta cognates.

ABSTRACT: Oligomeric amyloid ? (A?) is currently considered the most neurotoxic form of the A? peptide implicated in Alzheimer's disease (AD). The molecular structures of the oligomers have remained mostly unknown due to their transient nature. As a result, the molecular mechanisms of interactions between conformation-specific antibodies and their A? oligomer (A?O) cognates are not well understood. A monoclonal conformation-specific antibody, m5E3, was raised against a structural epitope of A? oligomers. m5E3 binds to A?Os with high affinity, but not to A? monomers or fibrils. In this study, a computational model of the variable fragment (Fv) of the m5E3 antibody (Fv5E3) is introduced. We further employ docking and molecular dynamics simulations to determine the molecular details of the antibody-oligomer interactions, and to classify the A?Os as Fv5E3-positives and negatives, and to provide a rationale for the low affinity of Fv5E3 for fibrils. This information will help us to perform site-directed mutagenesis on the m5E3 antibody to improve its specificity and affinity toward oligomeric A? species. We also provide evidence for the possible capability of the m5E3 antibody to disaggregate A?Os and to fragment protofilaments.

SUBMITTER: Khorvash M

PROVIDER: S-EPMC7259632 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Molecular interactions between monoclonal oligomer-specific antibody 5E3 and its amyloid beta cognates.

Khorvash Massih M Blinov Nick N Ladner-Keay Carol C Lu Jie J Silverman Judith M JM Gibbs Ebrima E Wang Yu Tian YT Kovalenko Andriy A Wishart David D Cashman Neil R NR

PloS one 20200529 5

Oligomeric amyloid β (Aβ) is currently considered the most neurotoxic form of the Aβ peptide implicated in Alzheimer's disease (AD). The molecular structures of the oligomers have remained mostly unknown due to their transient nature. As a result, the molecular mechanisms of interactions between conformation-specific antibodies and their Aβ oligomer (AβO) cognates are not well understood. A monoclonal conformation-specific antibody, m5E3, was raised against a structural epitope of Aβ oligomers. ...[more]

PMID: 32469918

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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

Molecular interactions between monoclonal oligomer-specific antibody 5E3 and its amyloid beta cognates.

Publications

Molecular interactions between monoclonal oligomer-specific antibody 5E3 and its amyloid beta cognates.

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