First structural Elucidation of Bcl-2 functional conversion induced by validated modulators using microsecond-scale...

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• Cancer is a leading cause of death, characterized by uncontrolled cell growth and resistance to apoptosis.
• The Bcl-2 protein family regulates apoptosis; anti-apoptotic Bcl-2 promotes cancer cell survival.
• Bcl-2 functional converters (BFCs) can reprogram Bcl-2 to induce apoptosis, but mechanisms are unclear.

Purpose of the Study:

• To elucidate the atomistic structural and dynamic mechanisms of Bcl-2 functional conversion mediated by targeting its flexible loop domain (FLD).
• To provide direct molecular evidence for how FLD targeting induces conformational changes in Bcl-2.

Main Methods:

• Molecular docking was used to assess binding of BFCs to Bcl-2.
• Atomistic microsecond-scale molecular dynamics (MD) simulations were performed to analyze binding stability and conformational dynamics.
• Key interactions between BFCs and FLD residues were investigated.

Main Results:

• BFCs (BFC1103 & BFC1108) exhibited strong binding affinity and stable interactions with key FLD residues.
• MD simulations revealed that FLD engagement induces significant conformational changes in Bcl-2.
• These changes lead to the exposure of the BH3 domain, mimicking a pro-apoptotic Bax-like state.

Conclusions:

• This study provides the first structural framework linking FLD targeting to Bcl-2 functional conversion.
• The findings bridge experimental data with atomistic simulations, explaining the mechanism of BFC action.
• This work offers a rational basis for designing novel anticancer therapeutics that restore apoptosis.