Exploring the Role of BCL2 Interactome in Cancer: A Protein/Residue Interaction Network Analysis

BCL2 is a critical regulator of intrinsic and extrinsic pathways of apoptosis that have been implicated in cancer progression and therapeutic resistance. In this study, the protein-protein interactions (PPIs) of BCL2 with potential binding partners and their role in cancer was investigated. A comprehensive PPI network for BCL2 has been generated by using the Protein Interactions Network Analysis (PINA) platform to identify key interactors. To further investigate the network, Molecular Operating Environment (MOE), Search Tool for the Retrieval of Interacting Genes (STRING), Residue Interaction Network Generation (RING), and the gProfiler server were used. Docking and Molecular Dynamics (MD) simulations were performed by using HDOCK and Gromacs to analyze the binding dynamics and stability of protein complexes. The BCL2 interactome revealed that three key interactors (p53, RAF1, and MAPK1) are involved in cancer-related processes. Docking studies highlighted BCL2 residues such as ASP111, ASP140, ARG107, and ARG146 that were predominantly involved in multiple hydrogen bonds, ionic interactions, and van der Waals contacts, highlighting conserved binding sites that play critical roles in the stability and specificity of protein-protein interactions. MD simulations (200 ns) of the BCL2-p53 complex showed that the RMSD was increased, suggesting the suppression of BCL2's anti-apoptotic activity by p53. The RMSD for BCL2-RAF1 was also increased, showing protein domain structural rearrangements that enhance BCL2 anti-apoptotic activity. The BCL2-MAPK1 complex revealed structural, distinct flexibility patterns and dynamic hydrogen bonding interactions. These findings provide valuable insights into the molecular dynamics by which BCL2 modulates apoptosis and its potential as a promising therapeutic in cancer and apoptosis-related diseases.