SuperStar: Comparison of CSD and PDB-based interaction fields as a basis for the prediction of protein-ligand interactions

SuperStar is an empirical method for identifying interaction sites in prote ins, based entirely on the experimental information about non-bonded intera ctions, present in the IsoStar database. The interaction information in Iso Star is contained in scatterplots, which show the distribution of a chosen probe around structure fragments. SuperStar breaks a template molecule (e.g . a protein binding site) into structural fragments which correspond to tho se in the scatterplots. The scatterplots are then superimposed on the corre sponding parts of the template and converted into a composite propensity ma p. The original version of SuperStar was based entirely on scatterplots from t he CSD. Here, scatterplots based on protein-ligand interactions are impleme nted in SuperStar, and validated on a test set of 122 X-ray structures of p rotein-ligand complexes. In this validation, propensity maps are compared w ith the experimentally observed positions of ligand atoms of comparable typ es. Although non-bonded interaction geometries in small molecule structures are similar to those found in protein-ligand complexes, their relative fre quencies of occurrence are different. Polar interactions are more common in the first class of structures, while interactions between hydrophobic grou ps are more common in protein crystals. In general, PDB and CSD-based Super Star maps appear equally successful in the prediction of protein-ligand int eractions. PDB-based maps are more suitable to identify hydrophobic pockets , and inherently take into account the experimental uncertainties of protei n atomic positions. If the protonation state of a histidine, aspartate or g lutamate protein side-chain is known, specific CSD-based maps for that prot onation state are preferred over PDB-based maps which represent an ensemble of protonation states. (C) 2001 Academic Press.