Congo red has been used to identify amyloid fibrils in tissues for more than 80 years and is also a weak inhibitor to both amyloid-β fibril formation and toxicity. However, the specificity of the binding and its inhibition mechanism remain unclear. Using all-atom molecular dynamics simulations with the explicit solvent model, we have identified and characterized two specific binding modes of Congo red molecules to a protofibril formed by an amyloidogenic fragment (GNNQQNY) of the yeast prion protein Sup35. The observation of dual-mode was consistent with the experimentally observed dual-mode binding to Aβ fibrils by a series of compounds similar to Congo red. In the primary mode, Congo red bound to a regular groove formed by the first three residues (GNN) of the β-strands along the β-sheet extension direction. Comparative simulations demonstrated that Thioflavin T also bound to the grooves on KLVFFAE protofibril surface. Because of the ubiquitous long grooves on the amyloid fibril surface, we propose that this binding interaction could be a general recognition mode of amyloid fibrils by Congo red, Thioflavin T, and other long flat molecules. In the secondary mode, Congo red bound parallel to the β-strands on the edge or in the middle of a β-sheet. The primary binding mode of Congo red and GNNQQNY protofibril was more stable than the secondary mode by -5.7 kcal/mol as estimated by the MM-GBSA method. Detailed analysis suggests that the hydrophobic interactions play important roles for burial of the hydrophobic part of the Congo red molecules. Two potential inhibition mechanisms of disrupting β-sheet stacking were inferred from the primary mode, which could be exploited for the development of non-peptidic amyloid-specific inhibitors.
All Science Journal Classification (ASJC) codes
- Colloid and Surface Chemistry