Docking‐based approach for identification of mutations that disrupt binding between Bcl‐2 and Bax proteins: Inducing apoptosis in cancer cells

BACKGROUND: Inducing apoptosis in cancer cells is an important step for the successful treatment of cancer patients. Bcl‐2 is an antiapoptotic protein which determines apoptosis by interacting with proapoptotic members of the Bcl‐2 family. Exome sequencing has identified Bcl‐2 and Bax missense mutations in more than 40 cancer types. However, a little information is available about the functional impact of each Bcl‐2 and Bax mutation on the pathogenesis of cancer. METHODS: The mutational data from cancer tissues and cell lines were retrieved from the cBioPortal web resource. The 13 mutated Bcl‐2 and wild‐type Bax complexes with experimentally verified binding were identified from previous studies wherein, binding for all complexes was reportedly disrupted except one. Several protein–protein docking methods such as ClusPro, HDOCK, PatchDock, FireDock, InterEVDock2 and several mutation prediction methods such as PolyPhen‐2, SIFT, and OncoKB have been used to predict the effect of mutation to disrupt the binding between Bcl‐2 and Bax. The result obtained was compared with the known experimental data. RESULTS: The protein–protein docking method, ClusPro, employed in the present study confirmed that the binding affinity of 11 out of 13 complexes decreases. Similarly, binding affinity computed for all the 10 wild‐type Bcl‐2 and mutated Bax complexes agreed with experimentally verified results. CONCLUSION: Several methods like PolyPhen‐2, SIFT, and OncoKB have been developed to predict cancer‐associated or deleterious mutations, but no method is available to predict apoptosis‐inducing mutations. Thus, in this study, we have examined the mutations in Bcl‐2 and Bax proteins that disrupt their binding, which is crucial for inducing apoptosis to eradicate cancer. This study suggests that protein–protein docking methods can play a significant role in the identification of hotspot mutations in Bcl‐2 or Bax that can disrupt their binding with wild‐type partner to induce apoptosis in cancer cells.