Polymorphic Triple beta-Sheet Structures Contribute to Amide Hydrogen/Deuterium (H/D) Exchange Protection in the Alzheimer Amyloid beta 42 Peptide

Characterization of the polymorphic structural range of A beta oligomers is important to the understanding of the mechanisms of toxicity. Yet for highly polymorphic ensembles, experimental structural elucidation is difficult. Here, we use a combination of NMR solvent protection experiments and computational structural screening to identify major species in the amyloid conformational ensemble. We examined the polymorphic pentamer and fibril seeds of A beta 42 and its mutants and compared the theoretical backbone amide protection obtained from simulations with experimental hydrogen/deuterium (H/D) exchange protection ratio. Weobserved that highly flexible pentamers do not share structural similarities with fibril seed oligomers, except the turn regions. We found that a novel amyloid structural motif of a triple beta-sheet, with the N-terminal residues interacting with the core (Lys(17)-Glu(22)) beta-sheet region, correlates with H/D exchange protection. The triple beta-sheet A beta 42 oligomer has a minimal exposure of hydrophobic residues and is further stabilized by the E22Q (Dutch) mutation in Alzheimer disease. The experimental H/D exchange solvent protection ratio implies that triple beta-sheet fibrils and globulomers could coexist in the A beta 42 ensemble, pointing to a broad heterogeneous aggregate population. Our results suggest that an approach that combines computational modeling with NMR protection data can be a useful strategy for obtaining clues to the preferred conformational species of the assemblies in solution and help in alleviating experimental difficulties and consequently possible errors in the exchange data for A beta 42 fibrils.

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