Complex disruption effect of natural polyphenols on Bcl-2-Bax: molecular dynamics simulation and essential dynamics...

Area of Science:

• Biochemistry
• Molecular Biology
• Cell Biology

Background:

• Apoptosis, or programmed cell death, is crucial for physiological function and preventing damage.
• The Bcl-2 protein family regulates apoptosis.
• Anti-apoptotic protein Bcl-2 inhibits Bax activation, preventing cytochrome c release from mitochondria.

Purpose of the Study:

• To investigate the interaction of natural polyphenols, quercetin and taxifolin, with Bcl-2.
• To determine the effect of these compounds on the Bcl-2-Bax complex.
• To compare the efficacy of quercetin and taxifolin in modulating Bcl-2 activity.

Main Methods:

• Molecular dynamics (MD) simulations were used to study the binding of quercetin and taxifolin to Bcl-2.
• The dissociation of the Bcl-2-Bax complex induced by these compounds was analyzed using MD simulations.
• Control simulations with ligand-unbound Bcl-2-Bax and the inhibitor obatoclax were performed.

Main Results:

• Quercetin and taxifolin bind to the hydrophobic groove of Bcl-2, inducing conformational changes.
• Taxifolin demonstrated higher interaction energy and greater collapse of the hydrophobic groove compared to quercetin.
• Both compounds effectively dissociated the Bcl-2-Bax complex during 12 ns MD simulations.
• The Bcl-2-Bax complex remained stable without quercetin or taxifolin.
• Obatoclax, a Bcl-2 inhibitor, did not significantly affect the Bcl-2-Bax complex stability.

Conclusions:

• Quercetin and taxifolin can disrupt the Bcl-2-Bax complex, suggesting a role in apoptosis regulation.
• Taxifolin is a more potent modulator of Bcl-2 structure and function than quercetin.
• These findings support the potential of natural polyphenols as therapeutic agents targeting apoptosis pathways.