%0 Journal Article
%A Olubiyi, Olujide
%A Frenzel, Daniel
%A Bartnik, Dirk
%A Glück, Julian
%A Brener, O.
%A Nagel-Steger, Luitgard
%A Funke, S. A.
%A Willbold, Dieter
%A Strodel, Birgit
%T Amyloid Aggregation Inhibitory Mechanism of Arginine-rich D-peptides
%J Current medicinal chemistry
%V 21
%@ 1875-533X
%C Hilversum [u.a.]
%I Bentham Science Publ.
%M FZJ-2014-02980
%P 1448-1457
%D 2014
%Z Campus-weite Veröffentlichung erwünschtD. Willbold und B. Strodel sind beide "Corresponding Authors".
%X 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.
%F PUB:(DE-HGF)16
%9 Journal Article
%U <Go to ISI:>//WOS:000333274400005
%U https://juser.fz-juelich.de/record/153348