Differences in β-strand Populations of Monomeric Aβ40 and Aβ42

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