ABSTRACT
It is widely believed that Alzheimer's disease pathogenesis is driven by the production and deposition of the amyloid-ß peptide (Aß) 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 Aß monomer and a fibrillar Aß structure. Results obtained from both molecular simulations and surface plasmon resonance experiments reveal a strong binding of D3 and RD2 to Aß, leading to a significant reduction in the amount of ß structures in both monomer and fibril, which was also demonstrated in Thioflavin T assays. The binding of the D-peptides to Aß is driven by electrostatic interactions, mostly involving the D-arginine residues and Glu11, Glu22 and Asp23 of Aß. 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 Aß, as well as the Aß oligomer size.
Subject(s)
Amyloid/metabolism , Peptides/chemistry , Amyloid/chemistry , Arginine/chemistry , Humans , Hydrophobic and Hydrophilic Interactions , Kinetics , Models, Molecular , Peptides/metabolism , Protein Binding , Protein Structure, Secondary , Protein Structure, TertiaryABSTRACT
The influence of ultra-violet and visible radiation (UV/VIS) on the read-out obtained from the main dosimetry peak of CaSO4:Dy in Teflon discs exposed to the gamma-radiation levels measured by a personnel-monitoring service has been studied as a function of wavelength, irradiance and radiant exposure. The results have been explained by the net effect of three separate factors, namely (i) an inherent response, (ii) a phototransfer and (iii) an optical bleaching. The response obtained from unirradiated discs illuminated with fluorescent room lighting became saturated after 16 hrs at a value corresponding to 0.33 microC kg-1 whilst gamma-irradiated discs faded to 90% of their initial exposure for the same illumination period.
