The Alzheimer’s Peptides Aβ40 and 42 Adopt Distinct Conformations in Water: A Combined MD / NMR Study

The role of peptides Aβ40 and Aβ42 in the early pathogenesis of Alzheimer's disease (AD) is frequently emphasized in the literature. It is known that Aβ42 is more prone to aggregation than Aβ40, even though they differ in only two (IA) amino acid residues at the C-terminal end. A direct comparison of the ensembles of conformations adopted by the monomers in solution has been limited by the inherent flexibility of the unfolded peptides. Here, we characterize the conformations of Aβ40 and Aβ42 in water by using a combination of molecular dynamics (MD) and measured scalar 3 J HNHα data from NMR experiments. We perform replica exchange MD (REMD) simulations and find that classical forcefields reproduce the NMR data quantitatively when the sampling is extended to the microseconds time-scale. Using the quantitative agreement of the NMR data as a validation of the model, we proceed to compare the conformational ensembles of the Aβ40 and Aβ42 peptide monomers. Our analysis confirms the existence of structured regions within the otherwise flexible Aβ peptides. We find that the C terminus of Aβ42 is more structured than that of Aβ40. The formation of a β-hairpin in the sequence 31 IIGLMVG GVVIA involving short strands at residues 31–34 and 38–41 (in bold) reduces the C-terminal flexibility of the Aβ42 peptide and may be responsible for the higher propensity of this peptide to form amyloids.