curcumin and exifone

Amyloid fibrils are highly ordered protein aggregates associated with many diseases affecting millions of people worldwide. Polyphenols such as Curcumin, Exifone, and Myricetin exhibit modest inhibition toward fibril formation of tau peptide which is associated with Alzheimer's disease. However, the molecular mechanisms of this inhibition remain elusive. We investigated the binding of three polyphenol molecules to the protofibrils of an amyloidogenic fragment VQIVYK of tau peptide by molecular dynamics simulations in explicit solvent. We find that polyphenols induce conformational changes in the oligomer aggregate. These changes disrupt the amyloid H bonding, perturbing the aggregate. While the structural evolution of the control oligomer with no ligand is limited to the twisting of the β-sheets without their disassembly, the presence of polyphenol molecule pushes the β-sheets apart, and leads to a loosely packed structure where two of four β-sheets dissociate in each of the three cases considered here. The H-bonding capacity of polyphenols is responsible for the observed behavior. The calculated binding free energies and its individual components enabled better understanding of the binding. Results indicated that the contribution from Van der Waals interactions is more significant than electrostatic contribution to the binding. The findings from this study are expected to assist in the development of aggregation inhibitors. Significant binding between polyphenols and aggregate oligomer identified in our simulations confirms the previous experimental observations in which polyphenols refold the tau peptide without forming covalent bonds.

Topics: Amino Acid Sequence; Amyloid; Benzophenones; Curcumin; Flavonoids; Humans; Hydrogen Bonding; Models, Molecular; Molecular Conformation; Molecular Dynamics Simulation; Peptide Fragments; Polyphenols; Protein Aggregation, Pathological; Protein Binding; Protein Multimerization; Quantitative Structure-Activity Relationship; tau Proteins