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

ABSTRACT

The soluble oligomeric form of the amyloid beta (Aß) 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 Aß. Here we introduce the multi-parametric surface plasmon resonance (MP-SPR) approach to quantify SLF binding and effect on the self-association of the peptide via a label-free, real-time approach. Kinetic analysis of SLF binding to Aß and measurements of layer thickness alterations inform on the mechanism underlying the ability of SLF to inhibit Aß toxicity and its progression towards larger oligomeric assemblies. Depending on the oligomeric state of Aß, distinct binding affinities for SLF are revealed. The Aß monomer and dimer uniquely possess sub-nanomolar affinity for SLF via a non-specific mode of binding. SLF binding is weaker in oligomeric Aß, which displays an affinity for SLF on the order of 100 µM. To complement these experiments we carried out molecular docking and molecular dynamics simulations to explore how SLF interacts with the Aß peptide. The MP-SPR results together with in silico modeling provide affinity data for the SLF-Aß interaction and allow us to develop a new general method for examining protein aggregation.