Automated benchmarking of combined protein structure and ligand conformation prediction

The prediction of protein-ligand complexes (PLC), using both experimental and predicted structures, is an active and important area of research, underscored by the inclusion of the Protein-Ligand Interaction category in the latest round of the Critical Assessment of Protein Structure Prediction experiment CASP15. The prediction task in CASP15 consisted of predicting both the 3-dimensional structure of the receptor protein as well as the position and conformation of the ligand. This paper addresses the challenges and proposed solutions for devising automated benchmarking techniques for PLC prediction. The reliability of experimentally solved PLC as ground truth reference structures is assessed using various validation criteria. Similarity of PLC to previously released complexes are employed to judge the novelty and difficulty of a PLC as a prediction target. We show that the commonly used PDBBind time-split test-set is inappropriate for comprehensive PLC evaluation. Finally, we introduce a fully automated pipeline that predicts PLC and evaluates the accuracy of the protein structure, ligand pose, and protein-ligand interactions.