Townsend, David John and Hughes, Eleri and Stewart, Katie and Griffin, John Matthew and Radford, Sheena and Middleton, David Andrew (2018) Orientation of a Diagnostic Ligand Bound to Macroscopically Aligned Amyloid-β Fibrils Determined by Solid-State NMR. The Journal of Physical Chemistry Letters, 9 (22). 6611–6615. ISSN 1948-7185
paper_formatted.pdf - Accepted Version
Available under License Creative Commons Attribution-NonCommercial.
Download (649kB)
Abstract
With amyloid diseases poised to become a major health burden in countries with ageing populations, diagnostic molecules that aid the detection of amyloid in vitro and in vivo are of considerable clinical value. Understanding how such ligands recognize their amyloid targets would help to design diagnostics that target specific amyloid types associated with a particular disease, but methods to provide comprehensive information are underdeveloped. Here solid-state NMR is used to determine the molecular orientation of the amyloid diagnostic 1-fluoro-2,5-bis[(E)-3-carboxy-4-hydroxystyryl]-benzene (FSB) when bound to fibrils of the Alzheimer’s amyloid-β polypeptide aligned on a planar substrate. The 19F NMR spectrum of the aligned complex reveals that FSB is oriented approximately parallel with the fibril long axis and bridges four hydrogen-bonded β-sheets. In addition to providing atomic details to aid the design of amyloid-specific diagnostics, this approach will also illuminate the molecular mechanisms of accessory molecules in amyloid disease.