Structural Artifacts in Protein−Ligand X-ray Structures: Implications for the Development of Docking Scoring Functions

The development of docking scoring functions requires high-resolution 3D structures of protein−ligand complexes for which the binding affinity of the ligand has been measured experimentally. Protein−ligand binding affinities are measured in solution experiments, and high resolution protein−ligand structures can be determined only by X-ray crystallography. Protein−ligand scoring functions must therefore reproduce solution binding energies using analyses of proteins in a crystal environment. We present an analysis of the prevalence of crystal-induced artifacts and water-mediated contacts in protein−ligand complexes and demonstrate the effect that these can have on the performance of protein−ligand scoring functions. We find 36% of ligands in the PDBBind 2007 refined data set to be influenced by crystal contacts and find the performance of a scoring function to be affected by these. A Web server for detecting crystal contacts in protein−ligand complexes is available at http://enzyme.ucd.ie/LIGCRYST.