Inhibition of amyloid-(16-22) aggregation by polyphenols using replica permutation with solute tempering molecular dynamics simulation

Aggregates of amyloid-beta (A beta) peptides are thought to cause Alzheimer's disease. Polyphenolic compounds are known to inhibit A beta aggregation. We applied replica permutation with solute tempering (RPST) to the system of A beta fragments, A beta(16-22), and polyphenols to elucidate the mechanism of inhibition of A beta aggregation. The RPST molecular dynamics simulations were performed for two polyphenols, myricetin (MYC) and rosmarinic acid (ROA). Two A beta fragments were distant, and the number of residues forming the intermolecular beta-sheet was reduced in the presence of MYC and ROA compared with that in the absence of polyphenols. MYC was found to interact with glutamic acid and phenylalanine of A beta fragments. These interactions induce helix structure formation of A beta fragments, making it difficult to form beta-sheet. ROA interacted with glutamic acid and lysine, which reduced the hydrophilic interaction between A beta fragments. These results indicate that these polyphenols inhibit the aggregation of A beta fragments with different mechanisms.