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

Abstract

This paper is dedicated to a good colleague and friend, Ted Sorensen, on the occasion of his 75th birthday AbstractThe 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.

Cu2+ Affects Amyloid-β (1–42) Aggregation by Increasing Peptide-Peptide Binding Forces

“…In our control experiments without copper, we observe two distinct force peaks most likely associated with different dimer configurations, possibly parallel and anti-parallel for two amyloid peptides interacting with each other at the self-recognition site as proposed by Tjernberg [46,47] and illustrated in figures 5A and B. The anti-parallel dimer configuration (Figure 5A) is the more stable of the two stabilized by salt bridges at each end [48], and therefore, we assign this configuration to the stronger force observed (peak two, Figure 2A). The first weaker force (peak one, Figure 2A) more likely corresponds to the parallel configuration (Figure 5B).…”

Pseudopeptide Amyloid Aggregation Inhibitors: In Silico, Single Molecule and Cell Viability Studies

“…Ligand-docking protocols and steered MD simulations were used to calculate a predicted affinity between the SG inhibitor and the target Aβ(13–23), the self-recognition region (R) of the peptide HHQKLVFFAED [ 33 ]. In the computational studies, the self-recognition region, Aβ(13–23), is expected to be very flexible, with a hairpin turn between V18 and F19, forming an intramolecular β-sheet; this hairpin turn is stabilized by intramolecular interactions between the carboxylate group of E22 and the backbone N-H bonds of V18, F19 and F20 [ 28 , 33 , 57 ]. Computational studies demonstrated that the SG inhibitors have a rigid backbone in comparison to Aβ(13–23), due to the N-methylated amine backbone which cannot form intramolecular hydrogen bonds and that the SG-R complex prevents the hairpin turn of Aβ(13–23) increasing rigidity ( Figure 2 ) [ 21 , 28 , 30 , 31 ].…”

“…Various substitutions of the SG inhibitor are made to maximize affinity for Aβ13–23. N-terminal substitution of γ-diaminobutyric acid may improve interactions with D23 on Aβ; substitution of lysine in the KLVFF sequence with ornithine may improve electrostatic side chain interactions with E22 [ 33 , 57 ]. Other improvements to peptide inhibitors can be made by substituting various lipophilic aromatic residues, which may optimize hydrophobic interactions between the drug and Aβ target [ 58 , 59 ].…”

Copper(I) Chelators for Alzheimer’s Disease

“…Thus, the combinations PP–PI0 , PP–SI1 , and PP–SI2 should serve the dual functions of reducing the copper-induced toxicity of Aβ as well as preventing its aggregation into toxic oligomers. Preliminary work on several classes of PP has appeared. − …”