Evaluation of a knowledge-based potential of mean force for scoring dockedprotein-ligand complexes

The Biomolecular Ligand Energy Evaluation Protocol (BLEEP) is a knowledge-b ased potential derived from high-resolution X-ray structures of protein-lig and complexes. The performance of this potential in ranking the hypothetica l structures resulting from a docking study has been evaluated using fiftee n protein-ligand complexes from the Protein Data Bank. Ln the majority of c omplexes BLEEP was successful in identifying the native (experimental) bind ing mode or an alternative of low rms deviation (from the native) as the lo west in energy. Overall BLEEP is slightly better than the DOCK energy funct ion in discriminating native-like modes. Even when alternative binding mode s rank lower than the native structure, a reasonable energy is assigned to the latter. Breaking down the BLEEP scores into the atom-atom contributions reveals that this type of potential is grossly dominated by longer range i nteractions (>5 Angstrom), which makes it relatively insensitive to small l ocal variations in the binding site. However, despite this limitation, the lack, at present, of accurate protein-ligand potentials means that BLEEP is a promising approach to improve the filtering of structures resulting from docking programs. Moreover, BLEEP should improve with the continuously inc reasing number of complexes available in the PDB. (C) 2001 John Wiley & Son s, Inc.