The role of phenolic OH groups of flavonoid compounds with H-bond formation ability to suppress amyloid mature fibrils by destabilizing [beta]-sheet conformation of monomeric A[beta]17-42

Alzheimer's disease (AD) is a kind of brain disease that arises due to the aggregation and fibrillation of amyloid [beta]-peptides (A[beta]). The peptide A[beta]17-42 forms U-shape protofilaments of amyloid mature fibrils by cross-[beta] strands, detected in brain cells of individuals with AD. Targeting the structure of A[beta]17-42 and destabilizing its [beta]-strands by natural compounds could be effective in the treatment of AD patients. Therefore, the interaction features of monomeric U-shape A[beta]17-42 with natural flavonoids including myricetin, morin and flavone at different mole ratios were comprehensively studied to recognize the mechanism of A[beta] monomer instability using molecular dynamics (MD) simulations. We found that all flavonoids have tendency to interact and destabilize A[beta] peptide structure with mole ratio-dependent effects. The interaction free energies of myricetin (with 6 OHs) and morin (with 5 OHs) were more negative compared to flavone, although the total binding energies of all flavonoids are favorable and negative. Myricetin, morin and flavone penetrated into the core of the A[beta]17-42 and formed self-clusters of A[beta]17-42-flavonoid complexes. Analysis of A[beta]17-42-flavonoids interactions identified that the hydrophobic interactions related to SASA-dependent energy are weak in all complexes. However, the intermolecular H-bonds are a main binding factor for shifting U-shape rod-like state of A[beta]17-42 to globular-like disordered state. Myricetin and morin polyphenols form H-bonds with both peptide's carbonyl and amine groups whereas flavone makes H-bonds only with amine substitution. As a result, polyphenols are more efficient in destabilizing [beta]-sheet structures of peptide. Accordingly, the natural polyphenolic flavonoids are useful in forming stable A[beta]17-42-flavonoid clusters to inhibit A[beta]17-42 aggregation and these compounds could be an effective candidate for therapeutically targeting U-shape protofilaments' monomer in amyloid mature fibrils.