Docking and scoring with alternative side-chain conformations

We describe a scoring and modeling procedure for docking ligands into protein models that have either modeled or flexible side-chain conformations. Our methodical contribution comprises a procedure for generating new potentials of mean force for the ROTA scoring function which we have introduced previously for optimizing side-chain conformations with the tool IRECS. The ROTA potentials are specially trained to tolerate small-scale positional errors of atoms that are characteristic of (i) side-chain conformations that are modeled using a sparse rotamer library and (ii) ligand conformations that are generated using a docking program. We generated both rigid and flexible protein models with our side-chain prediction tool IRECS and docked ligands to proteins using the scoring function ROTA and the docking programs FlexX (for rigid side chains) and FlexE (for flexible side chains). We validated our approach on the forty screening targets of the DUD database. The validation shows that the ROTA potentials are especially well suited for estimating the binding affinity of ligands to proteins. The results also show that our procedure can compensate for the performance decrease in screening that occurs when using protein models with side chains modeled with a rotamer library instead of using X-ray structures. The average runtime per ligand of our method is 168 seconds on an Opteron V20z, which is fast enough to allow virtual screening of compound libraries for drug candidates.