Aggregation of Aβ(17–36) in the Presence of Naturally Occurring Phenolic Inhibitors Using Coarse-Grained Simulations. Issue 24 (8th December 2017)

• Record Type: Journal Article
• Authors: Wang, Yiming; Latshaw, David C.; Hall, Carol K.
• Is Part Of: Journal of molecular biology. Volume 429:Issue 24(2017)
• Page Start: 3893
• Page End: 3908
• Publication Date: 2017-12-08
• Subjects: discontinuous molecular dynamics -- protein aggregation -- polyphenol -- amyloid β -- inhibitory mechanism; Aβ amyloid β protein -- AD Alzheimer's disease -- DMD discontinuous molecular dynamics -- EGCG epigallocatechin-3-gallate; Molecular biology -- Periodicals; Biology -- Periodicals; Biochemistry -- Periodicals; Bacteriology -- Periodicals; Molecular Biology -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biologie -- Périodiques; Biochimie -- Périodiques; Moleculaire biologie; Biochemistry; Biology; Molecular biology; Periodicals; 572.805
• DOI: 10.1016/j.jmb.2017.10.006
• Languages: English
• ISSNs: 0022-2836

Abstract

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. Graphical Abstract: Highlights: We examine the effect of four phenolic inhibitors on Aβ(17–36) aggregation. We build a coarse-grained inhibitor model into the original PRIME20 force field. Eight Aβ(17–36) peptides aggregate to form a U-shaped protofilament. Three polyphenolic inhibitors redirect eight Aβ(17–36)s to form disordered oligomers. Polyphenols with rigid stereo configurations are potential amyloid inhibitors.