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Biophysical and Computational Insights into Alpha-1 Antitrypsin Aggregation and Its Inhibition by Natural Polyphenols
Tarique Sarwar1, Ahmed Abdur Rehman2, Hussain Arif2
1Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia.
Biomedicines
|June 26, 2026
Summary
Natural polyphenols amentoflavone (AMF) and theaflavin (TF) inhibit alpha-1 antitrypsin (A1AT) misfolding and aggregation induced by trifluoroethanol (TFE). AMF and TF show potential as therapeutic scaffolds against amyloidogenic processes.
Area of Science:
- Biochemistry and Molecular Biology
- Protein Misfolding and Aggregation
- Neurodegenerative Disease Research
Background:
- Protein misfolding and amyloid fibril formation are implicated in diseases like Alzheimer's and Parkinson's.
- Alpha-1 antitrypsin (A1AT) misfolding and aggregation are linked to A1AT deficiency and related disorders.
- Trifluoroethanol (TFE) is used to induce structural changes and aggregation in proteins.
Purpose of the Study:
- To investigate the structural changes in A1AT induced by TFE.
- To evaluate the inhibitory effects of natural polyphenols amentoflavone (AMF) and theaflavin (TF) on A1AT aggregation.
- To explore the potential of AMF and TF as anti-aggregation agents.
Main Methods:
- Virtual screening of phytocompounds against A1AT structure using AutoDock Vina.
- Induction of A1AT aggregation with TFE and assessment of polyphenol inhibition using various biochemical assays (protease activity, fluorescence, turbidity, scattering).
- Molecular dynamics simulations and MM-PBSA calculations to analyze protein-ligand interactions and complex stability.
Main Results:
- AMF and TF significantly inhibited TFE-induced A1AT aggregation in a dose-dependent manner, with AMF being more potent.
- ThT fluorescence assays showed ~60-65% reduction in aggregate formation, with IC50 values of ~40 µM for AMF and ~50 µM for TF.
- Molecular docking and simulations confirmed stable interactions between A1AT and polyphenols, with AMF showing stronger binding and better attenuation of conformational changes.
Conclusions:
- TFE induces A1AT misfolding via a molten globule intermediate, leading to fibril formation.
- AMF and TF effectively inhibit A1AT aggregation in a concentration-dependent manner.
- AMF and TF show promise as lead scaffolds for developing anti-aggregation strategies and modulating amyloidogenic processes.
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