Assisted assignment of ligands corresponding to unknown electron density
A semi-automated computational procedure to assist in the identification of bound ligands from unknown electron density has been developed. The atomic surface surrounding the density blob is compared to a library of three-dimensional ligand binding surfaces extracted from the Protein Data Bank (PDB). Ligands corresponding to surfaces which share physicochemical texture and geometric shape similarities are considered for assignment. The method is benchmarked against a set of well represented ligands from the PDB, in which we show that we can identify the correct ligand based on the corresponding binding surface. Finally, we apply the method during model building and refinement stages from structural genomics targets in which unknown density blobs were discovered. A semi-automated computational method is described which aims to assist crystallographers with assigning the identity of a ligand corresponding to unknown electron density. Using shape and physicochemical similarity assessments between the protein surface surrounding the density and a database of known ligand binding surfaces, a plausible list of candidate ligands are identified for consideration. The method is validated against highly observed ligands from the Protein Data Bank and results are shown from its use in a high-throughput structural genomics pipeline.
KeywordsElectron density assignment Function annotation Ligand identification Ligand assignment Protein surfaces
We would like to thank all members of the Midwest Center for Structural Genomics for helpful discussion and access to crystallographic data. The benchmarking studies were performed on the Argonne Leadership Computing Facilities’ BlueGene/P computing system as part of the Department of Energy’s INCITE program. This work was supported by National Institutes of Health Grants GM62414 and GM074942 and by the US Department of Energy, Office of Biological and Environmental Research, under contract DE-AC02-06CH11357.
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