Molecular alignment within sheets in A_14-23 fibrils: solid state NMR experiments and theoretical predictions

¹ Fox Chase Cancer Center
² New York University School of Medicine
³ National Institutes of Health

^* To whom correspondence should be addressed. E-mail: robertt{at}niddk.nih.gov.

Submitted on June 8, 2006
Revised on July 21, 2006
Accepted on 2 October 2006

	Abstract

We report investigations of the molecular structure of amyloid fibrils formed by residues 14-23 of the -amyloid peptide associated with Alzheimer's disease (A_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_14-23 fibrils contain antiparallel -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 -sheet. We compare these results, as well as previously reported experimental results for fibrils formed by other -amyloid fragments, with theoretical predictions of molecular alignment based on databases of residue-specific alignments in antiparallel -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.

Key Words: Alzheimer's disease, amyloid, protein structure, solid state NMR

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