Simulations on the dual effects of flavonoids as suppressors of Aβ42 fibrillogenesis and destabilizers of mature fibrils

Structural studies of the aggregation inhibition of the amyloid-beta peptide (A beta) by different natural compounds are of the utmost importance due to their great potential as neuroprotective and therapeutic agents for Alzheimer's disease. We provided the simulation of molecular dynamics for two different states of A beta 42, including monomeric aggregation-prone state (APS) and U-shaped pentamers of amyloidogenic protofilament intermediates in the absence and presence of polyphenolic flavonoids (Flvs, myricetin and morin) in order to verify the possible mechanism of Flvs fibrillogenesis suppression. Data showed that Flvs directly bind into A beta 42 species in both states of monomeric APS beta -sheets and pentameric amyloidogenic intermediates. Binding of Flvs with amyloidogenic protofilament intermediates caused the attenuation of some inter-chains H-bonds, salt bridges, van der Waals and interpeptide interaction energies without interfering with their secondary beta -sheets. Therefore, Flvs redirect oligomeric amyloidogenic intermediates into unstructured aggregates by significant disruption of the steric zipper motif of fibrils-pairs of self-complementary beta -sheets-without changing the amount of beta -sheets. It is while Flvs completely destruct the disadvantageous secondary beta -sheets of monomeric APS conformers by converting them into coil/helix structures. It means that Flvs suppress the fibrillogenesis process of the monomeric APS structures by converting their beta -sheets into proper soluble coil/helices structures. The different actions of Flvs in contact with two different states of A beta conformers are related to high interaction tendency of Flvs with additional H-bonds for monomeric APS beta -sheet, rather than oligomeric protofilaments. Linear interaction energy (LIE) analysis confirmed the strong binding of monomeric A beta -Flvs with more negative G(binding,) rather than oligomeric A beta -Flvs system. Therefore, atomic scale computational evaluation of Flvs actions demonstrated different dual functions of Flvs, concluded from the application of two different monomeric and pentameric A beta 42 systems. The distinct dual functions of Flvs are proposed as suppressing the aggregation by converting beta -sheets of monomeric APS to proper soluble structures and disrupting the steric zipper fibril motifs of oligomeric intermediate by converting on-pathway into off-pathway. Taken together, our data propose that Flvs exert dual and more effective functions against monomeric APS (fibrillogenesis suppression) and remodel the A beta aggregation pathway (fibril destabilization).