Here it is. It’s finally happening. I’m actually writing a blog post about docking. Are the end times upon us? Perhaps. If by my next post I’m not back to my usual techie self, the horsemen may well be on their way.
If you’ve ever used, read about, or listened to a lab mate complain about protein-ligand docking, you’re likely familiar with the rigid receptor assumption. In this model, the active site of the protein is treated as completely rigid, with no side chain flexibility, and only the rotatable bonds in the ligand are allowed to move. The motivation behind this assumption is simple. The computational cost of sampling the conformational space of a ligand within a protein’s active site, and doing so with sufficient rigour so as to sample a near-native binding mode, grows rapidly with the number of rotatable bonds in the ligand. Further increasing the degrees of freedom in the system by incorporating receptor side chain flexibility compounds this problem, making the sampling of accurate binding modes for the ligand an incredibly expensive and difficult problem.
One compromise, if multiple structures with different active site conformations are available for the target protein, is to simply dock your ligands into multiple structures, and trust your scoring function (!!!) to pick out the best binding mode from across the different structures. This is a crude approximation to true flexible receptor docking which won’t capture fully any induced fit effects due to a particular ligand, but if the structures are available, this may offer a more computationally-feasible alternative to flexible docking.
A study earlier this year by Cleves and Jain illustrates this approach nicely. They dock the ligands of the DUD-E database into multiple structures for each target, in each case treating the receptor strucutre as completely rigid. Unsurprisingly, when the target is rigid and there is little structural variation in the active site across the structures, the choice of structure has little influence on the docking results. However, when the receptor is flexible, with clear structural variation across the active sites in the different structures, there is a strong impact on the poses generated by rigid-receptor docking. This effect translates directly into improved virtual screening performance when docking into multiple different structures, illustrating the value of considering the conformational space of the receptor, even when it is treated as rigid during the docking process.
