d-Amino Acid Pseudopeptides as Potential Amyloid-Beta Aggregation Inhibitors.

A causative factor for neurotoxicity associated with Alzheimer's disease is the aggregation of the amyloid-ß (Aß) peptide into soluble oligomers. Two all d-amino acid pseudo-peptides, SGB1 and SGD1, were designed to stop the aggregation. Molecular dynamics (MD) simulations have been carried out to study the interaction of the pseudo-peptides with both Aß13⁻23 (the core recognition site of Aß) and full-length Aß1⁻42. Umbrella sampling MD calculations have been used to estimate the free energy of binding, ∆G, of these peptides to Aß13⁻23. The highest ∆Gbinding is found for SGB1. Each of the pseudo-peptides was also docked to Aß1⁻42 and subjected up to seven microseconds of all atom molecular dynamics simulations. The resulting structures lend insight into how the dynamics of Aß1⁻42 are altered by complexation with the pseudo-peptides and confirmed that SGB1 may be a better candidate for developing into a drug to prevent Alzheimer's disease.

Testing synthetic amyloid-ß aggregation inhibitor using single molecule atomic force spectroscopy.

Alzheimer's disease is a neurodegenerative disease with no known cure and few effective treatment options. The principal neurotoxic agent is an oligomeric form of the amyloid-ß peptide and one of the treatment options currently being studied is the inhibition of amyloid aggregation. In this work, we test a novel pseudopeptidic aggregation inhibitor designated as SG1. SG1 has been designed to bind at the amyloid-ß self-recognition site and prevent amyloid-ß from misfolding into ß sheet. We used atomic force spectroscopy, a nanoscale measurement technique, to quantify the binding forces between two single amyloid peptide molecules. For the first time, we demonstrate that single molecule atomic force spectroscopy can be used to assess the effectiveness of amyloid aggregation inhibitors by measuring the experimental yield of binding and can potentially be used as a screening technique for quick testing of efficacy of inhibitor drugs for amyloid aggregation.