Design of peptidyl compounds that affect β-amyloid aggregation:: Importance of surface tension and contex

Self-association of beta-amyloid (A beta) peptide into cross-beta-sheet fibrils induces cellular toxicity in vitro and is linked with progression of Alzheimer's disease. Previously, we demonstrated that hybrid peptides, containing a recognition domain that binds to A beta and a disrupting domain consisting of a chain of charged amino acids, inhibited A beta-associated toxicity in vitro and increased the rate of A beta aggregation. In this work we examine the design parameter space of the disrupting domain. Using KLVFFKKKKKK as a base case, we tested hybrid compounds with a branched rather than linear lysine oligomer, with L-lysine replaced by D-lysine, and with lysine replaced by diaminopropionic acid. We synthesized a compound with a novel anionic disrupting domain that contained cysteine thiols oxidized to sulfates, as well as other compounds in which alkyl or ether chains were appended to KLVFF. In all cases, the hybrid compound's ability to increase solvent surface tension was the strongest predictor of its effect on A beta aggregation kinetics. Finally, we investigated the effects of arginine on A beta aggregation. Arginine is a well-known chaotrope but increases surface tension of water. Arginine modestly decreased A beta aggregation. In contrast, RRRRRR slightly, and KLVFFRRRRRR greatly, increased A beta aggregation. Thus, the influence of arginine on A beta aggregation depends strongly on the context in which it is presented. The effect of arginine, RRRRRR, and KLVFFRRRRRR on A beta aggregation was examined in detail using laser light scattering, circular dichroism spectroscopy, Fourier transform infrared spectroscopy, thioflavin T fluorescence, and transmission electron microscopy.