Oligomers of the prion protein fragment 106-126 are likely assembled from beta-hairpins in solution, and methionine oxidation inhibits assembly without altering the peptide's monomeric conformation.

A portion of the prion protein, PrP106-126, is highly conserved among various species and is thought to be one of the key domains involving amyloid formation of the protein. We used ion mobility spectrometry-mass spectrometry (IMS-MS) in conjunction with replica exchange molecular dynamics (REMD) to examine the monomeric and oligomeric structures of normal PrP106-126 and two nonaggregating forms of the peptide, an oxidized form in which both methionine residues are oxidized to methionine sulfoxide and a control peptide consisting of the same amino acids as PrP106-126 in a scrambled sequence. Our ion mobility and simulation data indicate the presence of a population of beta-hairpin monomers for the normal and oxidized peptides. This is supported by our CD data indicating that a monomer solution of the normal peptide contains approximately 46% beta-sheet and approximately 23% beta-turn content, in excellent agreement with our REMD simulations. Oligomerization was seen by IMS-MS for the normal peptide only, not the oxidized peptide or the control sequence. Both our IMS-MS and CD data suggest that this oligomerization results from the association of ordered beta-hairpin monomers rather than disordered monomers. Structural analysis shows that the normal and oxidized peptides have similar secondary and tertiary structural properties, suggesting that the inhibition of aggregation caused by methionine oxidation stems from mediating interpeptide interactions rather than by altering the peptide's monomeric conformation. In contrast, an increase in alpha-helical and random coil structural components relative to the normal peptide might be responsible for the lack of observed aggregation of the control peptide.