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Molecular Alignment within ß-Sheets in Aß_14-23 Fibrils: Solid-State NMR Experiments and Theoretical Predictions

Zimei Bu ^*, Yuan Shi , David J. E. Callaway ^*  and Robert Tycko 

^* Fox Chase Cancer Center, Philadelphia, Pennsylvania; New York University School of Medicine, New York, New York; and Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland

Correspondence: Address reprint requests to R. Tycko, E-mail: robertt{at}niddk.nih.gov; or D. Callaway, david.callaway{at}fccc.edu.

We report investigations of the molecular structure of amyloid fibrils formed by residues 14–23 of the ß-amyloid peptide associated with Alzheimer's disease (Aß_14-23), using solid-state nuclear magnetic resonance (NMR) techniques in conjunction with electron microscopy and atomic force microscopy. The NMR measurements, which include two-dimensional proton-mediated ¹³C-¹³C exchange and two-dimensional relayed proton-mediated ¹³C-¹³C exchange spectra, show that Aß_14-23 fibrils contain antiparallel ß-sheets with a registry of backbone hydrogen bonds that aligns residue 17+k of each peptide molecule with residue 22–k of neighboring molecules in the same ß-sheet. We compare these results, as well as previously reported experimental results for fibrils formed by other ß-amyloid fragments, with theoretical predictions of molecular alignment based on databases of residue-specific alignments in antiparallel ß-sheets in known protein structures. While the theoretical predictions are not in exact agreement with the experimental results, they facilitate the design of experiments by suggesting a small number of plausible alignments that are readily distinguished by solid-state NMR.

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