100 ns molecular dynamics simulations to study intramolecular conformational changes in Bax

Area of Science:

• Molecular Biology
• Biochemistry
• Cell Biology

Background:

• Bax is a pro-apoptotic protein in the Bcl-2 family, regulated by anti-apoptotic proteins like Bcl-x(L).
• Intra-molecular conformational changes in Bax are essential for Bcl-x(L) regulation and mitochondrial translocation.

Purpose of the Study:

• To investigate the intra-molecular conformational changes of Bax in an aqueous environment using molecular dynamics.
• To understand the structural transitions Bax undergoes before mitochondrial membrane insertion.

Main Methods:

• Detailed molecular dynamics simulations of Bax in an aqueous environment.
• Analysis of fluctuations in full-length and deletion mutant Bax simulations.
• Identification of hydrogen bonding patterns and water-mediated interactions across Bax domains.

Main Results:

• Observed distinct movement of Bax's N-terminal end during 100ns simulations.
• Identified hydrogen bonding between the N-terminal region and the BH2 domain (alpha(7, 8)).
• BH2 domain formed new hydrogen bonds with transmembrane helices (TM1), mediated by water molecules.

Conclusions:

• The structural alliance between Bax's N-terminal region and BH2 domain suggests a transition cascade.
• This cascade leads to the dislocation of transmembrane helices from the BH3 domain.
• These conformational changes are critical for Bax's function in apoptosis and mitochondrial membrane insertion.