Molecular Alignment within β-Sheets in A β14-23 Fibrils: Solid-State NMR Experiments and Theoretical Predictions

Abstract

We report investigations of the molecular structure of amyloid fibrils formed by residues 14–23 of the β-amyloid peptide associated with Alzheimer’s disease (A β 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 A β 14-23 fibrils contain antiparallel β-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 β-sheet. We compare these results, as well as previously reported experimental results for fibrils formed by other β-amyloid fragments, with theoretical predictions of molecular alignment based on databases of residue-specific alignments in antiparallel β-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.