Project Abstract:

Docking reactions play an important role in a large number of biochemical processes. Docking results can help researchers gain insight into the mechanism of action of therapeutically interesting proteins, which is of critical importance in the area of rational approaches to drug development and treatment of disease. Bcl-2 is an ‘antiapoptotic’ protein which has been linked to diseases like cancer. It has been observed that Bcl-2 is over-expressed in many cancer cells and in turn provide resistance to treatment of cancer with radiation and chemotherapeutic agents. Recent work indicates that Bcl-2 functions as a pro-oxidant in cancer cells, thereby creating an intracellular milieu non-permissive for the execution of the death signal.

One of the intracellular mediators of super-oxide production is the membrane NADPH oxidase complex, the assembly of which is brought about by a small GTP binding protein, Rac1. It needs to be investigated if the pro-oxidant activity of Bcl-2 is a result of Bcl-2- Rac1 docking. Experimental results have confirmed the existence of a functional complex between the two in the mitochondria. In addition to this a domain(BH3 domain in Bcl-2) specific interaction with Rac1 is observed. Identification of the binding domains within these proteins will not only enhance our understanding of the functional significance of the interaction, but will also have potential implications for the design and development of novel therapies to enhance cancer cell response to drug treatment. We look at the proteins Bcl-2 and Rac1 and use computational tools to confirm the docking between these two proteins and then identify the interacting domains within them. We use the web server CLUSPRO and the ‘Protein-Protein Interaction server’ (PPI) to model the binding affinity of Bcl-2 in an attempt to decipher the precise interacting domains within Bcl-2 and Rac1 and in turn provide a structural basis for the observed reaction.