Residue-level structural information from isotope-edited FTIR spectroscopy reveals distinct molecular structures of different amyloid-β42 oligomers

Oligomers of the amyloid-{beta} peptide 1-42 (A{beta}42) are one of the underlying causes of pathogenicity in Alzheimers disease. However, investigating their molecular structure is challenging with common structural biology techniques. In this work we employed isotope-edited Fourier transform infrared spectroscopy with site-specific labeling, an advanced method enabling collection of residue-level structural information on oligomers of all sizes in aqueous solution. The A{beta}42 peptides studied comprised those that were 13C, 15N-labeled at either residue V18, F20, A30, or I32, as well as those doubly-labeled at V18 and A30, at F20 and A30, and at F20 and I32. We studied three types of oligomers. For A{beta}42 oligomers prepared in the absence of detergents, all labeled residues are positioned within {beta}-strands. Moreover, in these oligomers intramolecular vibrational coupling was detected between residues V18 and A30, as well as F20 and A30, in addition to intermolecular coupling between V18 amides, and between F20 and I32 residues. This indicates that these residues are close in the 3-dimensional structure (contact). By contrast, detergent-stabilized oligomers formed in the presence of low concentrations of sodium dodecyl sulfate have different structures: V18 and F20 are not incorporated in a {beta}-sheet, whereas A30 and I32 are found to reside in a {beta}-sheet. No interactions (contacts) were detected between any pair of labeled residues in detergent-stabilized A{beta}42 oligomers. We propose that in our oligomer preparations, V18 and F20 are stably incorporated into a {beta}-sheet only for oligomers that are larger than dodecamers.