Differences in β-strand populations of monomeric Aβ40 and Aβ42.

Using homonuclear (1)H NOESY spectra, with chemical shifts, (3)JH(N)H(α) scalar couplings, residual dipolar couplings, and (1)H-(15)N NOEs, we have optimized and validated the conformational ensembles of the amyloid-β 1-40 (Aβ40) and amyloid-β 1-42 (Aβ42) peptides generated by molecular dynamics simulations. We find that both peptides have a diverse set of secondary structure elements including turns, helices, and antiparallel and parallel β-strands. The most significant difference in the structural ensembles of the two peptides is the type of β-hairpins and β-strands they populate. We find that Aβ42 forms a major antiparallel β-hairpin involving the central hydrophobic cluster residues (16-21) with residues 29-36, compatible with known amyloid fibril forming regions, whereas Aβ40 forms an alternative but less populated antiparallel β-hairpin between the central hydrophobic cluster and residues 9-13, that sometimes forms a β-sheet by association with residues 35-37. Furthermore, we show that the two additional C-terminal residues of Aβ42, in particular Ile-41, directly control the differences in the β-strand content found between the Aβ40 and Aβ42 structural ensembles. Integrating the experimental and theoretical evidence accumulated over the last decade, it is now possible to present monomeric structural ensembles of Aβ40 and Aβ42 consistent with available information that produce a plausible molecular basis for why Aβ42 exhibits greater fibrillization rates than Aβ40.