Binding Modes of Thioflavin T and Congo Red to the Fibril Structure of Amyloid-β(1–42)

Binding modes for the amyloid-β(1-42) fibril tracers Thioflavin T and Congo red were predicted using unbiased molecular dynamics simulations and binding free energy calculations. The fluorescent dyes bind on the fibril surface to primarily hydro-phobic grooves, with their long axis oriented almost parallel to the fibril axis. The binding modes were corroborated with com-puted binding affinities, which are in agreement with experi-mental values. The binding modes also explain observables from previous structural studies. The binding modes provide a starting point for the systematic search and design of novel and improved molecules that bind to Aβ(1-42) fibrils, which may improve in vitro diagnostics for Alzheimer’s disease.