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

A causative factor for neurotoxicity associated with Alzheimer&rsquo
s disease is the aggregation of the amyloid-&beta
(A&beta
) 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 A&beta
13&ndash
23 (the core recognition site of A&beta
) and full-length A&beta
1&ndash
42. Umbrella sampling MD calculations have been used to estimate the free energy of binding, ∆G, of these peptides to A&beta
23. The highest ∆Gbinding is found for SGB1. Each of the pseudo-peptides was also docked to A&beta
42 and subjected up to seven microseconds of all atom molecular dynamics simulations. The resulting structures lend insight into how the dynamics of A&beta
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&rsquo
s disease.