Three Distinct Binding Modes Govern High-Affinity Ligand Interactions with Amyloid Fibrils

However, the rational design of small-molecule ligands and probes targeting these aggregates is limited by a poor understanding of how ligands bind to amyloid fibrils. This work outlines an experimental approach to determine the binding mode of ligands to amyloid fibrils using previously overlooked information contained within standard binding assays.

Using a mathematical framework to analyze binding behavior, three distinct high-affinity binding modes were identified: discrete, overlapping, and interacting binding. Reanalysis of published binding data indicates that these binding modes are widespread among common amyloid-binding ligand scaffolds. Two ligands were designed using principles informed by these binding modes, yielding improved binding affinities and characteristic fluorescence responses.