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Inhibition Mechanisms of (-)-Epigallocatechin-3-gallate and Genistein on Amyloid-beta 42 Peptide of Alzheimer's Disease via Molecular Simulations.

ABSTRACT: The misfolding and self-assembly of amyloid-beta (Aβ) peptides are one of the most important factors contributing to Alzheimer's disease (AD). This study aims to reveal the inhibition mechanisms of (-)-epigallocatechin-3-gallate (EGCG) and genistein on the conformational changes of Aβ42 peptides by using molecular docking and molecular dynamics (MD) simulation. The results indicate that both EGCG and genistein have inhibitory effects on the conformational transition of Aβ42 peptide. EGCG and genistein reduce the ratio of β-sheet secondary structures of Aβ42 peptide while inducing random coil structures. In terms of hydrophobic interactions in the central hydrophobic core of Aβ42 peptide, the binding affinities of EGCG are significantly larger in comparison with that of genistein. Our findings illustrate the inhibition mechanisms of EGCG and genistein on the Aβ42 peptides and prove that EGCG is a very promising inhibitor in impeding the conformational change of Aβ42 peptide.

SUBMITTER: Fang M

PROVIDER: S-EPMC9202277 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Inhibition Mechanisms of (-)-Epigallocatechin-3-gallate and Genistein on Amyloid-beta 42 Peptide of Alzheimer's Disease via Molecular Simulations.

Fang Mei M Zhang Quan Q Wang Xin X Su Kehe K Guan Ping P Hu Xiaoling X

ACS omega 20220531 23

The misfolding and self-assembly of amyloid-beta (Aβ) peptides are one of the most important factors contributing to Alzheimer's disease (AD). This study aims to reveal the inhibition mechanisms of (-)-epigallocatechin-3-gallate (EGCG) and genistein on the conformational changes of Aβ42 peptides by using molecular docking and molecular dynamics (MD) simulation. The results indicate that both EGCG and genistein have inhibitory effects on the conformational transition of Aβ42 peptide. EGCG and gen ...[more]

PMID: 35721940

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Project description:Numerous therapeutic agents and strategies were designed targeting the therapies of Alzheimer's disease, but many have been suspended due to their severe clinical side effects (such as encephalopathy) on patients. The attractiveness for small molecules with good biocompatibility is therefore restarted. Epigallocatechin-3-gallate (EGCG), extracted from green tea, is expected to be a promising small-molecule drug candidate, which can remodel the structure of preformed β-sheet-rich oligomers/fibrils and then effectively interfere with neurodegenerative processes. However, as the structure of non-fibrillary aggregates cannot be directly characterized, the atomic details of the underlying inhibitory and destructive mechanisms still remain elusive to date. Here, all-atom molecular dynamics simulations and experiments were carried out to elucidate the EGCG-induced remodeling mechanism of amyloid β (Aβ) fibrils. We showed that EGCG was indeed an effective Aβ fibril inhibitor. EGCG was capable of mediating conformational rearrangement of Aβ1-42 fibrils (from a β-sheet to a random coil structure) and triggering the disintegration of fibrils in a dose-dependent manner. EGCG redirected the structure of Aβ by breaking the β-sheet structure and hydrogen bonds between peptide chains within the Aβ protofibrils, especially the parallel β-strand (L17VFFAEDVGS26). Moreover, reduced solvent exposure and multisite binding patterns all tended to induce the conformation conversion of Aβ17-42 pentameric protofibrils, destroying pre-formed fibrils and inhibiting continued fibril growth. Detailed data analysis revealed that structural features of EGCG with abundant benzene ring and phenolic hydroxyl moieties preferentially interact with the parallel β-strands to effectually hinder the interaction of the interpeptide chain and the growth of the ordered β-sheet structure. Furthermore, experimental studies confirmed that EGCG was able to disaggregate the preformed fibrils and alter the protein structure. This study will enable a deeper understanding of fundamental principles for design of structural-based inhibitors.

Dataset Information

Inhibition Mechanisms of (-)-Epigallocatechin-3-gallate and Genistein on Amyloid-beta 42 Peptide of Alzheimer's Disease via Molecular Simulations.

Publications

Inhibition Mechanisms of (-)-Epigallocatechin-3-gallate and Genistein on Amyloid-beta 42 Peptide of Alzheimer's Disease via Molecular Simulations.

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