{'fraction_non_alphanumeric': 0.025936599423631124, 'fraction_numerical': 0.006340057636887608, 'mean_word_length': 5.177935943060498, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
BIM Binding Remotely Regulates BAX Activation: Insights from the Free Energy Landscapes

Activation of the pro-apoptotic BAX protein, a BCL-2 family member, is known to trigger apoptosis by forming pores in the mitochondrial outer membrane (MOM). While in the cytosol, release of its transmembrane C-terminal helix (called α9 helix) from a well-characterized binding pocket (BC groove) and subsequent permeabilization of the MOM are understood to be the initiating events of the activation. Concerning what initiates BAX activation, so far one plausible suggestion has been that the transient attachment of BH3-only peptide at a distal site from the BC groove triggers the activation process. Yet how this pivotal step displaces α9 from the BC groove has remained poorly understood. Using a combination of standard molecular dynamics and enhanced sampling methods, the energy landscape of BIM (BH3-only peptide) induced BAX activation has been computed, and the molecular origin of those events is hereby reported in atomistic detail. The simulated transition pathway of α9 release reveals that BIM subdues the energetic cost of the process by reducing the activation energy barrier to some extent but mostly by minimizing the free energy difference between the active (α9-released) and inactive (α9-bound) states. Interestingly, the flexibility of the α9 helix itself plays a decisive role in this mechanism. The impact of BIM encounter at the distal site is found to propagate to the α9 (BC groove bound) mostly through conserved pathways of residue level interactions. Overall, the thermodynamic basis of the "hit-and-run" mechanism for activation of the BCL-2 family is presented reconciling the available biochemical observations.