title: Amyloid aggregation inhibitory mechanism of arginine-rich D-peptides.
abstract: 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.
authors.forename: O O
authors.initials: OO
authors.lastname: Olubiyi
authors.forename: D
authors.initials: D
authors.lastname: Frenzel
authors.forename: D
authors.initials: D
authors.lastname: Bartnik
authors.forename: J M
authors.initials: JM
authors.lastname: Glück
authors.forename: O
authors.initials: O
authors.lastname: Brener
authors.forename: L
authors.initials: L
authors.lastname: Nagel-Steger
authors.forename: S A
authors.initials: SA
authors.lastname: Funke
authors.forename: D
authors.initials: D
authors.lastname: Willbold
authors.affiliation: Forschungszentrum Jülich, Institute of Complex Systems: Structural Biochemistry (ICS-6), 52425 Jülich, Germany. d.willbold@fz-juelich.de.
authors.forename: B
authors.initials: B
authors.lastname: Strodel
mesh_terms: D000682:Amyloid / Q000737:chemistry / Q000378:metabolism*; D001120:Arginine / Q000737:chemistry; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
chemical_list: D000682:Amyloid; D010455:Peptides; D001120:Arginine