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Published on: May 22, 2018
Inhibitory mechanisms of amentoflavone on amyloid-β peptide aggregation revealed by replica exchange molecular
Suxia Wu1, Chang Liu1, Yang Li1
1Hebei Normal University of Science and Technology, Qinhuangdao, 066600, Hebei, PR China.
Abstract:
Amyloid-β (Aβ) aggregation is a central pathological hallmark of Alzheimer's disease, with soluble trimers recognized as particularly neurotoxic species. Amentoflavone (AMF), a natural biflavonoid compound, has shown strong inhibitory effects on Aβ aggregation. However, its underlying molecular mechanism remains poorly understood. In this study, we employed replica exchange molecular dynamics (REMD) and molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) method to elucidate the interaction between AMF and Aβ peptides. Our results reveal that AMF preferentially binds to the 16KLVFFAEDV24 segment, a hydrophobic core that plays a critical role in the initiation of aggregation. It disrupts b-sheet formation through hydrophobic interactions with Leu-17, Phe-20, and Val-24. This binding stabilizes disordered coil conformations and prevents the conformational transitions required for fibril formation. Based on these findings, we performed structure-based virtual screening and identified two natural product-derived candidates with higher predicted affinity. These insights provide an atomic-level understanding of AMF's inhibitory mechanism and support the rational design of natural product-inspired inhibitors that target Aβ aggregation.
Insights
Amentoflavone inhibits Alzheimer's disease amyloid-β (Aβ) aggregation by stabilizing disordered conformations. This natural compound targets the Aβ peptide's aggregation-prone core, offering a potential strategy for developing new Alzheimer's therapies.
Area of Science:
- Neuroscience
- Biochemistry
- Pharmacology
Background:
- Amyloid-β (Aβ) aggregation is a key pathological feature of Alzheimer's disease.
- Soluble Aβ trimers are particularly neurotoxic species.
- The molecular mechanisms underlying Aβ aggregation inhibition by Amentoflavone (AMF) are not fully understood.
Purpose of the Study:
- To elucidate the molecular mechanism of Amentoflavone (AMF) in inhibiting amyloid-β (Aβ) aggregation.
- To understand the interaction between AMF and Aβ peptides at an atomic level.
- To identify potential natural product-derived inhibitors of Aβ aggregation.
Main Methods:
- Replica exchange molecular dynamics (REMD) simulations.
- Molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) calculations.
- Structure-based virtual screening.
Main Results:
- AMF preferentially binds to the 16KLVFFAEDV24 segment of Aβ.
- AMF disrupts β-sheet formation via hydrophobic interactions, stabilizing disordered coil conformations.
- Virtual screening identified two natural product-derived candidates with higher predicted binding affinity.
Conclusions:
- AMF inhibits Aβ aggregation by preventing conformational transitions essential for fibril formation.
- The study provides atomic-level insights into AMF's inhibitory mechanism.
- Findings support the rational design of natural product-inspired inhibitors targeting Aβ aggregation for Alzheimer's disease treatment.
