The mechanisms of flavonoids inhibiting conformational transition of amyloid-β42 monomer: a comparative molecular dynamics simulation study

Flavonoids can bind A beta(42) to inhibit the aggregation of A beta(42) monomer. However, the inhibitory mechanism remains unknown. Herein, comparable molecular dynamics simulations for a total of 710 ns were performed to study its mechanism. The in silico experiments revealed that flavonoids halt the conformational transition of A beta(42) monomer by inhibiting beta-sheet formation; the flavonoids push the residues D23 and K28 of A beta(42) to be exposed to solvated water, destroy the salt bridge between D23 and K28, induce the conformational distribution of A beta(42) into local minimization energy conformational state, and generate U-shaped A beta(42) configurations, which have more stable helixes and fewer unstable random coils. Moreover, simulation results from the free energy landscape and binding free energy analyses suggest that biflavonoids are superior to monoflavonoids in inhibiting conformational transition of A beta(42) monomer. These findings agree with the experimental data and may help in the design of new agents that will inhibit the conformational transition of A beta(42) so as to treat Alzheimer's disease.