Molecular-Scale Investigations Reveal the Effect of Natural Polyphenols on BAX/Bcl-2 Interactions

Apoptosis signaling controls the cell cycle through the protein-protein interactions (PPIs) of its major B-cell lymphoma 2-associated x protein (BAX) and B-cell lymphoma 2 protein (Bcl-2). Due to the antagonistic function of both proteins, apoptosis depends on a properly tuned balance of the kinetic...

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Published in:International journal of molecular sciences 2024-02, Vol.25 (5), p.2474
Main Authors: Sun, Heng, Liao, Fenghui, Tian, Yichen, Lei, Yongrong, Fu, Yuna, Wang, Jianhua
Format: Article
Language:English
Subjects:
Apoptosis
Atomic force microscopy
BAX/Bcl-2
bcl-2-Associated X Protein - metabolism
Catechin
Chemical bonds
Contact angle
Gossypol
Hydrogen
Lymphomas
Medical research
Molecular Docking Simulation
Physiology
Polyphenols
Polyphenols - pharmacology
Proteins
protein–protein interactions
Proto-Oncogene Proteins c-bcl-2 - metabolism
Rutin
Thermodynamics
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Summary:Apoptosis signaling controls the cell cycle through the protein-protein interactions (PPIs) of its major B-cell lymphoma 2-associated x protein (BAX) and B-cell lymphoma 2 protein (Bcl-2). Due to the antagonistic function of both proteins, apoptosis depends on a properly tuned balance of the kinetics of BAX and Bcl-2 activities. The utilization of natural polyphenols to regulate the binding process of PPIs is feasible. However, the mechanism of this modulation has not been studied in detail. Here, we utilized atomic force microscopy (AFM) to evaluate the effects of polyphenols (kaempferol, quercetin, dihydromyricetin, baicalin, curcumin, rutin, epigallocatechin gallate, and gossypol) on the BAX/Bcl-2 binding mechanism. We demonstrated at the molecular scale that polyphenols quantitatively affect the interaction forces, kinetics, thermodynamics, and structural properties of BAX/Bcl-2 complex formation. We observed that rutin, epigallocatechin gallate, and baicalin reduced the binding affinity of BAX/Bcl-2 by an order of magnitude. Combined with surface free energy and molecular docking, the results revealed that polyphenols are driven by multiple forces that affect the orientation freedom of PPIs, with hydrogen bonding, hydrophobic interactions, and van der Waals forces being the major contributors. Overall, our work provides valuable insights into how molecules tune PPIs to modulate their function.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms25052474