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Repurposing Triphenylmethane Dyes to Bind to Trimers Derived from Aβ

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    Repurposing Triphenylmethane Dyes to Bind to Trimers Derived from Aβ
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    Journal of the American Chemical Society

    Cite this: J. Am. Chem. Soc. 2018, 140, 37, 11745–11754
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    https://doi.org/10.1021/jacs.8b06568
    Published August 20, 2018
    Copyright © 2018 American Chemical Society
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    Abstract

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    Soluble oligomers of the β-amyloid peptide, Aβ, are associated with the progression of Alzheimer’s disease. Although many small molecules bind to these assemblies, the details of how these molecules interact with Aβ oligomers remain unknown. This paper reports that crystal violet, and other C3 symmetric triphenylmethane dyes, bind to C3 symmetric trimers derived from Aβ17–36. Binding changes the color of the dyes from purple to blue, and causes them to fluoresce red when irradiated with green light. Job plot and analytical ultracentrifugation experiments reveal that two trimers complex with one dye molecule. Studies with several triphenylmethane dyes reveal that three N,N-dialkylamino substituents are required for complexation. Several mutant trimers, in which Phe19, Phe20, and Ile31 were mutated to cyclohexylalanine, valine, and cyclohexylglycine, were prepared to probe the triphenylmethane dye binding site. Size exclusion chromatography, SDS-PAGE, and X-ray crystallographic studies demonstrate that these mutations do not impact the structure or assembly of the triangular trimer. Fluorescence spectroscopy and analytical ultracentrifugation experiments reveal that the dye packs against an aromatic surface formed by the Phe20 side chains and is clasped by the Ile31 side chains. Docking and molecular modeling provide a working model of the complex in which the triphenylmethane dye is sandwiched between two triangular trimers. Collectively, these findings demonstrate that the X-ray crystallographic structures of triangular trimers derived from Aβ can be used to guide the discovery of ligands that bind to soluble oligomers derived from Aβ.

    Copyright © 2018 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.8b06568.

    • Procedures for the synthesis of trimers 2; details of the crystallization, X-ray diffraction data collection, processing, and refinement of trimers 2; procedures for absorbance spectroscopy, fluorescence spectroscopy, analytical ultracentrifugation, isothermal titration calorimetry, SDS-PAGE, size exclusion chromatography, and Job’s method of continuous variation (PDF)

    • Structure of trimer 2I31V (PDB)

    • Structure of trimer 2I31Chg (PDB)

    • Structure of trimer 2F20Cha (PDB)

    • Crystallographic coordinates of trimer 2I31V (CIF)

    • Crystallographic coordinates of trimer 2I31Chg (CIF)

    • Crystallographic coordinates of trimer 2F20Cha (CIF)

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    Journal of the American Chemical Society

    Cite this: J. Am. Chem. Soc. 2018, 140, 37, 11745–11754
    Click to copy citationCitation copied!
    https://doi.org/10.1021/jacs.8b06568
    Published August 20, 2018
    Copyright © 2018 American Chemical Society
    Request reuse permissions

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