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

backgroundInducing 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.

methodsThe 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.

resultsThe 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.

conclusionSeveral 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.