Protein-Protein Docking for PROTAC discovery

My goal is to test whether structure-based approaches can guide the design of PROTACs. As a first step, I am evaluating whether protein-protein docking tools can accurately predict the interface between an E3 ligase and its target, a question recently explore by Drummond et al. This step is necessary to define the relative orientation of the chemical moiety binding the E3 ligase and the chemical moiety binding the target protein. Once we have this information, the second step will be to design PROTACs that are compatible with the relative orientation of these 2 chemical moieties. For this first protein-protein docking step, I will compare predicted structures with crystal structures of three complexes: the first bromodomain of BRD4 (BRD4BD1) bound to the E3 ligases CRBN [pdb codes 6boy and 6bnb], the second bromodomain of BRD4 (BRD4BD2) bound to the E3 ligase VHL [pdb code 5t35] and, the bromodomain of SMARCA2BD bound to the E3 ligase VHL [pdb code 6hay]. I will be using three different protein-protein docking tools: HADDOCK, Rosetta, and ICM, which all performed among the best at past CAPRI protein docking competitions.