Structures of the Amyloid\nβ-Peptides Aβ_1–40 and Aβ_1–42 as Influenced\nby pH and a d-Peptide

Abstract

In this simulation study, we present a comparison of\nthe secondary\nstructure of the two major alloforms of the Alzheimer’s peptide\n(Aβ_1–40 and Aβ_1–42) on the basis of molecular dynamics (MD) simulations on thea microsecond\ntime scale using the two GROMOS96 force fields ffG43a2 and ffG53a6.\nWe observe peptide and force-field related differences in the sampled\nconformations of Aβ_1–40 and Aβ_1–42, which we characterize in terms of NMR chemical shifts calculated\nfrom the MD trajectories and validate against the corresponding experimental\nNMR results. From this analysis, we can conclude that ffG53a6 is better\nable to model the structural propensities of Aβ_1–40 and Aβ_1–42 than ffG43a2. Furthermore, we\nprovide a description of the influences of pH and binding of D3, a\n12-residue d-enantiomeric peptide with demonstrated antiamyloid\neffects, on the structure of Aβ_1–42. We demonstrate\nthat, under slightly acidic conditions, protonation of the three histidine\nresidues in Aβ_1–42 promotes the formation\nof β-sheets via a reduction in electrostatic repulsion between\nthe two terminal regions. Our studies further reveal that the binding\nbetween D3 and Aβ_1–42 is driven by electrostatic\ninteractions between negatively charged Aβ_1–42 residues and the five positively charged arginine residues of D3.\nThe binding of D3 was found to induce large conformational changes\nin the amyloid peptide, with a reduction in β-sheet units being\nthe most significant effect recorded, possibly explaining the observed\namyloid-inhibiting properties of the d-peptide.