Structures of the amyloid β-peptides Aβ1-40 and Aβ1-42 as influenced by pH and a D-peptide.

In this simulation study, we present a comparison of the secondary structure of the two major alloforms of the Alzheimer's peptide (Aβ(1-40) and Aβ(1-42)) on the basis of molecular dynamics (MD) simulations on thea microsecond time scale using the two GROMOS96 force fields ffG43a2 and ffG53a6. We observe peptide and force-field related differences in the sampled conformations of Aβ(1-40) and Aβ(1-42), which we characterize in terms of NMR chemical shifts calculated from the MD trajectories and validate against the corresponding experimental NMR results. From this analysis, we can conclude that ffG53a6 is better able to model the structural propensities of Aβ(1-40) and Aβ(1-42) than ffG43a2. Furthermore, we provide a description of the influences of pH and binding of D3, a 12-residue D-enantiomeric peptide with demonstrated antiamyloid effects, on the structure of Aβ(1-42). We demonstrate that, under slightly acidic conditions, protonation of the three histidine residues in Aβ(1-42) promotes the formation of β-sheets via a reduction in electrostatic repulsion between the two terminal regions. Our studies further reveal that the binding between D3 and Aβ(1-42) is driven by electrostatic interactions between negatively charged Aβ(1-42) residues and the five positively charged arginine residues of D3. The binding of D3 was found to induce large conformational changes in the amyloid peptide, with a reduction in β-sheet units being the most significant effect recorded, possibly explaining the observed amyloid-inhibiting properties of the D-peptide.