Biflavonoid-Induced Disruption of Hydrogen Bonds Leads to Amyloid-β Disaggregation

Abstract

Deposition of amyloid β (Aβ) fibrils in the brain is a key pathologic hallmark of Alzheimer’s disease. A class of polyphenolic biflavonoids is known to have anti-amyloidogenic effects by inhibiting aggregation of Aβ and promoting disaggregation of Aβ fibrils. In the present study, we further sought to investigate the structural basis of the Aβ disaggregating activity of biflavonoids and their interactions at the atomic level. A thioflavin T (ThT) fluorescence assay revealed that amentoflavone-type biflavonoids promote disaggregation of Aβ fibrils with varying potency due to specific structural differences. The computational analysis herein provides the first atomistic details for the mechanism of Aβ disaggregation by biflavonoids. Molecular docking analysis showed that biflavonoids preferentially bind to the aromatic-rich, partially ordered N-termini of Aβ fibril via the p–p interactions. Moreover, docking scores correlate well with the ThT EC50 values. Molecular dynamic simulations revealed that biflavonoids decrease the content of β-sheet in Aβ fibril in a structure-dependent manner. Hydrogen bond analysis further supported that the substitution of hydroxyl groups capable of hydrogen bond formation at two positions on the biflavonoid scaffold leads to significantly disaggregation of Aβ fibrils. Taken together, our data indicate that biflavonoids promote disaggregation of Aβ fibrils due to their ability to disrupt the fibril structure, suggesting biflavonoids as a lead class of compounds to develop a therapeutic agent for Alzheimer’s disease.

Molecular mechanisms of amyloid disaggregation

“…Thus, the disruption of the Asp23-Lys28 salt bridge would lead to instability of the hydrogen bonds within the amino acid backbone that supports the fibrils and results in remodeling or disaggregation of the fibrils [85] . Using molecular docking (AutoDock Vina) and MD simulation with the disease-relevant Aβ fibril (PDB code: 2NAO), Windsor et al futher showed that the amentoflavone-type bioflavonoids disaggregate Aβ fibrils through the preferential binding to the N-terminal of the fibril via π-π interactions [89] , [90] . The aromatic rings of the compounds bind to the aromatic residues of the fibril and fit inside in the N-terminal pocket to stabilize the biflavonoid-fibril complex.…”

“…Subsequently, the hydrogen bond formation between the hydroxy groups at R2/R3 of the compound with the peptide backbone resulted in a large decrease in β sheet content of the fibril and altered the structural conformation of the Aβ fibril. Thus, resulting in the disaggregation of the fibril [90] . The mechanism of the amyloid disaggregation by the small compounds is schematically shown in Fig.…”

“…The purpose of molecular docking is to examine the binding mode between the amyloid fibrils and the disaggregating agent while the MD simulation aids in the detailed investigation of the detailed molecular interactions and the possible disaggregation mechanisms. These computational methods demonstrated that the direct interaction between disaggregating agents and amyloid fibrils which can either lead to instability within the fibril structure [76] , [85] , [90] , the conversion of the β sheet content within the fibril [98] , [120] or the direct insertion into the cavity of fibrils to disrupt fibril structure leading to fibril disaggregation [121] . The computational methods have the greatest advantage as they serve to explain the dynamics and molecular mechanism of amyloid disaggregation at an atomic level [122] ( Review ).…”

Identification of Catechins Binding Pockets in Monomeric Aβ42Through Ensemble Docking and MD Simulations

“…[11][12][18][19][20] For example, several computational and experimental observations have shown that polyphenolic plant compounds which occur naturally in fruit, vegetables, chocolate, and tea are capable of inhibiting IDP aggregation. [12][13][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] Finding aggregation inhibitors and direct targeting of monomeric IDPs via small molecules is a very active area of research and a wide variety of computational techniques have been applied, yet there are many inherent difficulties. 12-14, 27, 35-41 For example, most docking algorithms employ the flexible ligand and rigid receptor paradigm [42][43][44] but IDPs display high conformational heterogeneity, and ligand binding causes large structural changes in the IDP conformations.…”

Preparation of Synthetic and Natural Derivatives of Flavonoids Using Suzuki–Miyaura Cross-Coupling Reaction

“…Biflavonoids are flavonoid dimers consisting of two identical or non-identical flavonoid/flavone units linked by a C-C bond [25]. Biflavonoids have been reported to have anti-amyloidogenic effects by inhibiting aggregation of Aβ plaques and promoting the disaggregation of Aβ fibrils; this effect makes biflavonoids lead compounds in the treatment of Alzheimer's disease [26]. The preparation of biflavonoids using metal-catalyzed cross-coupling reactions has been previously reported in the literature.…”