Molecular dynamics study of the interaction of Aβ(13-23) with β-sheet inhibitors

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. Peptidic compounds intended to act as β-sheet inhibitors targeted to Aβ(13-23) have been shown to inhibit fibrillization of Aβ and also to reduce its neurotoxicity. We describe herein a study by molecular dynamics (MD) of the complexes between Aβ(13-23) and three (pseudo)peptidic β-sheet inhibitors, as well as its homodimer. The monomers of all systems exist predominantly as extended β-strands, with Aβ(13-23) having the greatest flexibility to adopt other conformations. The dimers of all systems exist almost exclusively as stable antiparallel β-sheets anchored at the C-terminus of Aβ(13-23) by salt bridges to the C-terminal residues, Glu22 and Asp23. We also employ an MD technique called "atomic force microscopy" (AFM) to examine the dynamics of dissociation of the complexes in water. Each ligand attached to Aβ(13-23) begins dissociation by peeling back from its C-terminus, breaking interstrand H-bonds, and losing the β-sheet character. The salt bridges are the last to release, and presumably are the first to form in the reverse process of aggregation. The free energy profiles of the dissociation as a function of the separation of the centers-of-mass of all systems show plateau regions in which separation takes place with relatively little or no rise in free energy. For each system the dissociation profile does not have a maximum and reaches a flat plateau. By implication, the reverse process of assembly does not have a barrier. This and the plateau regions in the dissociation profile are examples of entropy-enthalpy compensation that arise naturally during the AFM-MD simulation.