Molecular Alignment within β-Sheets in Aβ14-23 Fibrils: Solid-State NMR Experiments and Theoretical Predictions

We report investigations of the molecular structure of amyloid fibrils formed by residues 14-23 of the b-amyloid peptide associated with Alzheimer's disease (Ab14-23), 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 13 C- 13 C exchange and two-dimensional relayed proton-mediated 13 C- 13 C exchange spectra, show that Ab14-23 fibrils contain antiparallel b-sheets with a registry of backbone hydrogen bonds that aligns residue 171k of each peptide molecule with residue 22� k of neighboring molecules in the same b-sheet. We compare these results, as well as previously reported experimental results for fibrils formed by other b-amyloid fragments, with theoretical predictions of molecular alignment based on databases of residue-specific alignments in antiparallel b-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.