A novel modeling protocol for protein receptors guided by bound-ligand conformation

A novel protocol for protein homology modeling is described, in which uncertainty in protein structure is resolved by applying the criterion that the protein must bind to a complementary ligand. A diverse library of protein models is created and then screened by docking with ligands of known conformation. The more accurate protein models form higher-quality docked complexes, and the quality of the fit is used to select the best models. The effectiveness of this technique with both natural and unnatural ligands is demonstrated by modeling the Fv fragment of an antibody and comparing the results to known crystal structures.