It is widely believed that Alzheimer's disease pathogenesis is driven by the production and deposition of the
amyloid-β peptide (Aβ) in the brain. In this study, we employ a combination of in silico and in vitro approaches to investigate
the inhibitory properties of selected arginine-rich D-enantiomeric peptides (D-peptides) against amyloid aggregation.
The D-peptides include D3, a 12-residue peptide with anti-amyloid potencies demonstrated in vitro and in vivo, RD2,
a scrambled sequence of D3, as well as truncated RD2 variants. Using a global optimization method together with binding
free energy calculations followed by molecular dynamics simulations, we perform a detailed analysis of D-peptide binding
to Aβ monomer and a fibrillar Aβ structure. Results obtained from both molecular simulations and surface plasmon
resonance experiments reveal a strong binding of D3 and RD2 to Aβ, leading to a significant reduction in the amount of β
structures in both monomer and fibril, which was also demonstrated in Thioflavin T assays. The binding of the D-peptides
to Aβ is driven by electrostatic interactions, mostly involving the D-arginine residues and Glu11, Glu22 and Asp23 of Aβ.
Furthermore, we show that the anti-amyloid activities of the D-peptides depend on the length and sequence of the Dpeptide,
its ability to form multiple weak hydrophobic interactions with Aβ, as well as the Aβ oligomer size.
Amyloid beta, amyloid inhibition, D-peptides, in silico, surface plasmon resonance, ThT assay.
Forschungszentrum Jülich, Institute of Complex Systems: Structural Biochemistry (ICS-6), 52425 Jülich, Germany.