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Analytical Chemistry

Solid-State NMR Catches Protein Misfolding

New approach allows scientists to better track potential problems during solid-phase peptide synthesis

by Elizabeth K. Wilson
January 30, 2012 | A version of this story appeared in Volume 90, Issue 5

A new solid-state NMR technique to examine protein structure can visualize what might go awry during solid-phase peptide synthesis (SPPS) of long amino acid sequences (J. Am. Chem. Soc., DOI: 10.1021/ja212190z). Although SPPS is a ubiquitous lab tool for synthesizing peptides, chains with more than 30 amino acid residues are often difficult to synthesize presumably because peptides aggregate into misfolded clumps during the process. The structures of these aggregating chains have remained mysterious. Now, Songlin Wang and Yoshitaka Ishii of the University of Illinois, Chicago, have devised a variant of multidimensional solid-state NMR, known as 13C SSNMR, that can produce spectra that reveal the structure of proteins while they are bound to resin-based supports during SPPS. Their test subject was the well-characterized 40-residue amyloid-β peptide. Amyloid-β is unstructured in a monomer, but forms β-sheet-laden amyloid tangles in the brains of Alzheimer’s patients. Yet during SPPS, NMR spectra showed that the protein misfolded into highly rigid β-strand structures, illustrating the magnitude of the problem of SPPS synthesis of amyloid-β. The new NMR approach, the researchers note, “is likely applicable to a broad range of proteins” and may help the design of more efficient SPPS schemes.


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