Interaction of the N-AcAβ(13–23)NH2 segment of the beta amyloid peptide with beta-sheet-blocking peptides: site and edge specificity

Abstract

The region encompassing residues 13–23 of the amyloid beta peptide (Aβ(13–23)) of Alzheimer’s disease is the self-recognition site that initiates toxic oligomerization and fibrillization and also is the site of interaction of Aβ with many other proteins. We describe herein a study by molecular dynamics of the complexes formed by R (= N-AcAβ(13–23)NH2(N-CH3C(O)HHQKLVFFAEDNH2)) with several pseudopeptides designed to form β-sheets with Aβ(1-40,42) and prevent oligomer and fibril formation. Adhesion to both edges of the R β-strand is examined by structure analysis. Umbrella sampling along a dissociation pathway reveals approximate free energies of binding in the submicromolar range. One of the three pseudopeptides binds strongly to one edge of the R β-strand and another to the opposite edge, while the third displays strong binding to both edges. It is desirable to block both edges of the self-recognition site of Aβ to prevent oligomer formation. The study reveals that this may be accomplished by a single pseudopeptide or two in combination. Thus the pseudopeptides, used singly or in pairs, may be competitive inhibitors of Aβ oligomerization at stoichiometric concentrations.