Aggregation of Aβ(17-36) in the Presence of Naturally Occurring Phenolic Inhibitors Using Coarse-Grained Simulations

Although some naturally occurring polyphenols have been found to inhibit amyloid 3 (AB) fibril formation and reduce neuron cell toxicity in vitro, their exact inhibitory mechanism is unknown. In this work, discontinuous molecular dynamics combined with the PRIME20 force field and a newly built inhibitor model are performed to examine the effect of vanillin, resveratrol, curcumin, and epigallocatechin-3-gallate (EGCG) on the aggregation of AB(17-36) peptides. Four sets of peptide/inhibitor simulations are performed in which inhibitors (1) bind to AB(17-36) monomer (2) interfere with AB(17-36) oligomerization (3) disrupt a pre-formed A3(17-36) protofilament, and (4) prevent the growth of AB(17-36) protofilament. The single-ring compound, vanillin, slightly slows down but cannot inhibit the formation of a U-shaped AP(17-36) protofilament. The multiple-ring compounds, EGCG, resveratrol, and curcumin, redirect AB(17-36) from a fibrillar aggregate to an unstructured oligomer. The three aromatic groups of the EGCG molecule are in a stereo (nonplanar) configuration, helping it contact the N-terminal, middle, and C-terminal regions ofthe peptide. Resveratrol and curcumin bind only to the hydrophobic residues near peptide termini. The rank order of inhibitory effectiveness of AB(17-36) aggregation is as follows: EGCG >resveratrol >curcumin >vanillin, consistent with experimental findings on inhibiting full-length AB fibrillation. Furthermore, we learn that the inhibition effect of EGCG is specific to the peptide sequence, while those of resveratrol and curcumin are non-specific in that they stem from strong interference with hydrophobic side-chain association, regardless of the residues' location and peptide sequence. Our studies provide molecular-level insights into how polyphenols inhibit AB fibril formation, knowledge that could be useful for designing amyloid inhibitors. (c) 2017 Elsevier Ltd. All rights reserved.