Oligomerization Alters Binding Affinity between Amyloid Beta and a Modulator of Peptide Aggregation

摘要

The soluble oligomeric form of the amyloid beta (A beta) peptide is the major causative agent in the molecular pathogenesis of Alzheimer's disease (AD). We have previously developed a pyrroline-nitroxyl fluorene compound (SLF) that blocks the toxicity of A beta. Here we introduce the multiparametric surface plasmon resonance (MP-SPR) approach to quantify SLF binding and its effect on the self-association of the peptide via a label-free, real-time approach. Kinetic analysis of SLF binding to A beta and measurements of layer thickness alterations inform on the mechanism underlying the ability of SLF to inhibit A beta toxicity and its progression toward larger oligomeric assemblies. Depending on the oligomeric state of A beta, distinct binding affinities for SLF are revealed. The A beta monomer and dimer uniquely possess subnanomolar affinity for SLF via a nonspecific mode of binding. SLF binding is weaker in oligomeric A beta, which displays an affinity for SLF on the order of 100 mu M. To complement these experiments we carried out molecular docking and molecular dynamics simulations to explore how SLF interacts with the A beta peptide. The MP-SPR results together with in silico modeling provide affinity data for the SLF-A beta interaction and allow us to develop a new general method for examining protein aggregation.