Molecular Dynamics Study of the Binding of Cationic, Anionic, and Neutral Luminescent Conjugated Ligands to the Alzheimer Folds of A β (1–42) and Tau Fibrils

Unbiased atomistic molecular dynamics simulations have been employed to examine the binding interactions between amyloid fibrils (Aβ(1-42) and tau) with various ligands: anionic pFTAA, qFTAA-CN, neutral HS-276, and cationic bTVBT4. The ligand-fibril interactions were analyzed in a two-step approach. First, an analysis of the spatial distributions of the ligands around the amyloid fibril protofilaments was carried out to identify prospective binding sites. Second, the associated ligand-fibril binding energies at these sites were determined using umbrella sampling. The results reveal that pFTAA and qFTAA-CN share common binding sites in both Aβ(1-42) and tau fibrils. Ligands bTVBT4 and HS-276, on the other hand, are found to have different binding sites in Aβ(1-42) but share the same site in tau fibrils. An analysis of the spatial distributions of all ligand-fibril pair combinations under comparable conditions shows the lowest densities when bTVBT4 interacts with Aβ(1-42) and HS-276 with the tau fibril. These findings are corroborated by fluorescence costaining experiments, in which bTVBT4 and HS-276 show no correlation with Aβ-specific and tau-specific antibody markers, respectively. Further structural analysis reveals significant changes in the conformations of all ligands upon binding to the proteins compared to their conformations in aqueous solution. The binding of the anionic ligands (multiple localized negative charges) to fibrils is primarily driven by Coulombic forces, whereas the binding of the neutral HS-276 and cationic bTVBT4 (single delocalized positive charge) is governed by Lennard-Jones interactions. This highlights the influence of charges on binding, providing insights for the design of future ligands targeting Aβ(1-42) and tau fibrils.