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  • Title: Aggregation of Aβ(17-36) in the Presence of Naturally Occurring Phenolic Inhibitors Using Coarse-Grained Simulations.
    Author: Wang Y, Latshaw DC, Hall CK.
    Journal: J Mol Biol; 2017 Dec 08; 429(24):3893-3908. PubMed ID: 29031698.
    Abstract:
    Although some naturally occurring polyphenols have been found to inhibit amyloid β (Aβ) 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 Aβ(17-36) peptides. Four sets of peptide/inhibitor simulations are performed in which inhibitors (1) bind to Aβ(17-36) monomer (2) interfere with Aβ(17-36) oligomerization (3) disrupt a pre-formed Aβ(17-36) protofilament, and (4) prevent the growth of Aβ(17-36) protofilament. The single-ring compound, vanillin, slightly slows down but cannot inhibit the formation of a U-shaped Aβ(17-36) protofilament. The multiple-ring compounds, EGCG, resveratrol, and curcumin, redirect Aβ(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 of the peptide. Resveratrol and curcumin bind only to the hydrophobic residues near peptide termini. The rank order of inhibitory effectiveness of Aβ(17-36) aggregation is as follows: EGCG > resveratrol > curcumin > vanillin, consistent with experimental findings on inhibiting full-length Aβ 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 Aβ fibril formation, knowledge that could be useful for designing amyloid inhibitors.
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