Mapping the Binding Interface of PET Tracer Molecules and Alzheimer Disease Aβ Fibrils by Using MAS Solid-State NMR Spectroscopy.
Zheng NiuRiddhiman SarkarMichaela AichlerHans-Jürgen WesterBehrooz Hooshyar YousefiBernd ReifPublished in: Chembiochem : a European journal of chemical biology (2020)
Positron emission tomography (PET) tracer molecules like thioflavin T specifically recognize amyloid deposition in brain tissue by selective binding to hydrophobic or aromatic surface grooves on the β-sheet surface along the fibril axis. The molecular basis of this interaction is, however, not well understood. We have employed magic angle spinning (MAS) solid-state NMR spectroscopy to characterize Aβ-PET tracer complexes at atomic resolution. We established a titration protocol by using bovine serum albumin as a carrier to transfer hydrophobic small molecules to Aβ(1-40) fibrillar aggregates. The same Aβ(1-40) amyloid fibril sample was employed in subsequent titrations to minimize systematic errors that potentially arise from sample preparation. In the experiments, the small molecules 13 C-methylated Pittsburgh compound B (PiB) as well as a novel Aβ tracer based on a diarylbithiazole (DABTA) scaffold were employed. Classical 13 C-detected as well as proton-detected spectra of protonated and perdeuterated samples with back-substituted protons, respectively, were acquired and analyzed. After titration of the tracers, chemical-shift perturbations were observed in the loop region involving residues Gly25-Lys28 and Ile32-Gly33, thus suggesting that the PET tracer molecules interact with the loop region connecting β-sheets β1 and β2 in Aβ fibrils. We found that titration of the PiB derivatives suppressed fibril polymorphism and stabilized the amyloid fibril structure.
Keyphrases
- positron emission tomography
- solid state
- pet imaging
- computed tomography
- pet ct
- high resolution
- randomized controlled trial
- white matter
- ionic liquid
- mild cognitive impairment
- molecular docking
- multiple sclerosis
- patient safety
- tissue engineering
- mass spectrometry
- single molecule
- aqueous solution
- density functional theory
- brain injury
- resting state
- subarachnoid hemorrhage
- molecular dynamics simulations