Insights on the Binding of Thioflavin Derivative Markers to Amyloid-Like Fibril Models from Quantum Chemical Calculations

Thioflavin-T (ThT) is one of the most widely used dyes for staining and identifying amyloid fibrils, which share a common parallel in register β-sheet structure. Unfortunately, ThT is a charged molecule, which limits its ability to cross the blood brain barrier and its use as an efficient dye for in vivo detection of amyloid fibrils. For this reason, several uncharged ThT derivatives have been designed and their binding properties to Aβ fibrils studied by fluorescence assays. However, there are still many unknowns on the binding mechanism and the role of noncovalent interactions on the affinity of these ligands toward β-sheet structures. The present contribution analyzes the binding of ThT (1) and neutral ThT derivatives (2–7) to a β-sheet model by means of quantum chemical B3LYP-D calculations and including solvent effects with the continuum CPCM method. Results show that, in all cases, ligand binding is mainly driven by dispersion interactions. In addition, ligands with −NH groups display hydrogen bond interactions with CO groups of the peptide strand, increasing the intrinsic affinity toward the β-sheet surface. Solvent effects notably reduce the affinity of charged ThT, as compared to neutral systems, due to its larger solvation energy. As a result, neutral derivatives display significantly higher affinities than ThT in solution, in agreement with experimental observations. Analysis of the hydrogen bonding network of the β-sheet structure indicates that stacking interactions upon ligand binding induce a shortening of interstrand hydrogen bonding, suggesting a strengthening of the β-sheet.