P4‐343: Biophysical studies on the interactions of BETA‐AMYLOID and pseudopeptidic inhibitors of BETA‐AMYLOID oligomerization: Molecular dynamics simulations

Abstract

In Alzheimer's disease (AD) brain the amyloid beta (Aβ) peptide appears in senile plaques but the neurotoxic forms are soluble oligomers, most likely in association with redox active metals, e.g., copper. One way to stop Aβ neurotoxic activity is to prevent oligomerization and its interaction with copper. It was shown that Aβ binds to itself in the His13-Asp23 region of Aβ, and Cu +/Cu 2+ binds in the His13-His14 region. Aβ bound to copper incites processes that lead to the production of radicals responsible for death of neuron cells. In our lab several pseudopeptides (ligands) are designed to bind with Aβ (Lys16-Asp23) (S. Roy, PhD Dissertation, 2010). In order to avoid attack by antibodies the ligands are composed of eight amino acid residues. The ligands were designed to make antiparallel or parallel beta-sheets with Aβ (13–23), and are composed of both L- and D-handed residues. Selective N-methylation prevents propagation of the β-sheets into the toxic oligomeric form. This poster describes the results of a study using molecular dynamics simulations on the structures and energetic of the ligands and the ligand/Aβ (13–23) complexes, including estimates of the binding affinity of the ligands. We found that our ligands can compete successfully with Aβ(13–23) even though the dimerization interaction is relatively stronger. Cu(I) binds to His13 and His14. The effect of Cu(I)-binding to Ab is initially simulated by protonation of the His residues and the effects on ligand binding are reported. The results suggest modifications to the design to compete for the copper binding site of Aβ.