Issue 46, 2023

Single-molecule scale quantification reveals interactions underlying protein–protein interface: from forces to non-covalent bonds

Abstract

Protein–protein interactions (PPIs) between the B-cell lymphoma 2 (Bcl-2) family are considered a major driving force in cell cycle regulation and signaling. However, how this interfacial noncovalent interaction is achieved molecularly remains poorly understood. Herein, anti-apoptotic protein (Bcl-2) and pro-apoptotic protein (BAX) were used as models and their PPIs were explored for the first time using atomic force microscopy-based single-molecule force spectroscopy (SMFS) and in silico approaches. In addition, we used advanced analytical models, including multiple kinetic models, thermodynamic models, Poisson distributions, and contact angle molecular recognition to fully reveal the complexity of the BAX/Bcl-2 interaction interfaces. We propose that the binding kinetics between BAX/Bcl-2 are mainly mediated by specific (hydrogen bonding) and non-specific forces (hydrophobic interactions and electrostatic interactions) and show that the complicated multivalent binding interaction induces stable BAX/Bcl-2 complexes. This study enriches our understanding of the molecular mechanisms by which BAX interacts with Bcl-2. It provides valuable insights into the physical factors that need to be considered when designing PPI inhibitors.

Graphical abstract: Single-molecule scale quantification reveals interactions underlying protein–protein interface: from forces to non-covalent bonds

Supplementary files

Article information

Article type
Paper
Submitted
08 Sep 2023
Accepted
06 Nov 2023
First published
07 Nov 2023

Phys. Chem. Chem. Phys., 2023,25, 31791-31803

Single-molecule scale quantification reveals interactions underlying protein–protein interface: from forces to non-covalent bonds

H. Sun, Y. Tian, Y. Fu, Y. Lei, Y. Wang, X. Yan and J. Wang, Phys. Chem. Chem. Phys., 2023, 25, 31791 DOI: 10.1039/D3CP04351G

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