Searching the protein structure database for ligand-binding site similarities using CPASS v.2

Abstract

BackgroundA recent analysis of protein sequences deposited in the NCBI RefSeq database indicates that ~8.5 million protein sequences are encoded in prokaryotic and eukaryotic genomes, where ~30% are explicitly annotated as "hypothetical" or "uncharacterized" protein. Our Comparison of Protein Active-Site Structures (CPASS v.2) database and software compares the sequence and structural characteristics of experimentally determined ligand binding sites to infer a functional relationship in the absence of global sequence or structure similarity. CPASS is an important component of our Functional Annotation Screening Technology by NMR (FAST-NMR) protocol and has been successfully applied to aid the annotation of a number of proteins of unknown function.FindingsWe report a major upgrade to our CPASS software and database that significantly improves its broad utility. CPASS v.2 is designed with a layered architecture to increase flexibility and portability that also enables job distribution over the Open Science Grid (OSG) to increase speed. Similarly, the CPASS interface was enhanced to provide more user flexibility in submitting a CPASS query. CPASS v.2 now allows for both automatic and manual definition of ligand-binding sites and permits pair-wise, one versus all, one versus list, or list versus list comparisons. Solvent accessible surface area, ligand root-mean square difference, and Cβ distances have been incorporated into the CPASS similarity function to improve the quality of the results. The CPASS database has also been updated.ConclusionsCPASS v.2 is more than an order of magnitude faster than the original implementation, and allows for multiple simultaneous job submissions. Similarly, the CPASS database of ligand-defined binding sites has increased in size by ~ 38%, dramatically increasing the likelihood of a positive search result. The modification to the CPASS similarity function is effective in reducing CPASS similarity scores for false positives by ~30%, while leaving true positives unaffected. Importantly, receiver operating characteristics (ROC) curves demonstrate the high correlation between CPASS similarity scores and an accurate functional assignment. As indicated by distribution curves, scores ≥ 30% infer a functional similarity. Software URL: http://cpass.unl.edu.

Bioinformatics and variability in drug response: a protein structural perspective

“…Relibase offers tools for comparing ligand binding sites, analysing ligand similarity and searching for binding partners [287]. Similarly, CPASS database contains liganddefined protein active sites from structures in the PDB [228]. Furthermore, the Structural Biology Knowledgebase (SBKB) [288] and Therapeutic Targets Database (TTD) [289] enhance the study of protein-ligand interactions with information regarding three-dimensional protein structures, ligands, pathways and diseases.…”

“…Comparison of protein active site structures (CPASS) employs a straightforward alignment approach, exhaustively iterating translations and rotations of the query pattern to match a fixed target pattern [228]. More efficient methods group proximal pattern elements into triplets and optimally align these using geometric matching, as in ProSurfer [229], or geometric hashing, as in SiteEngines [230].…”

“…database URL three-dimensional protein structures CSA [278] http://www.ebi.ac.uk/thornton-srv/databases/CSA DCD [41] http://fpocket.sourceforge.net/dcd FireDB [279] http://firedb.bioinfo.cnio.es ModBase [280] http://modbase.compbio.ucsf.edu PDB [34] http://www.pdb.org protein model portal [281] http://www.proteinmodelportal.org sc-PDB [282] http://bioinfo-pharma.u-strasbg.fr/scPDB SitesBase [283] http://www.modelling.leeds.ac.uk/sb SWISS-MODEL repository [284] http://swissmodel.expasy.org/repository three-dimensional protein-ligand structures and interactions binding MOAD [285] http://www.bindingmoad.org CPASS [228] http://cpass.unl.edu DrugBank [48] http://www.drugbank.ca PDBbind [286] http://www.pdbbind.org Relibase [287] http://relibase.rutgers.edu SBKB [288] http://sbkb.org TTD [289] http://bidd.nus.edu.sg/group/cjttd/TTD.asp genetic variants & disease dbSNP [290] http://www.ncbi.nlm.nih.gov/snp catalogue of published GWAS [291] http://www.genome.gov/gwastudies OMIM [292] http://omim.org SCAN [293] http://www.scandb.org SwissVar [294] http://swissvar.expasy.org genetic variants and three-dimensional protein structures LS-SNP [295] http://ls-snp.icm.jhu.edu/ls-snp-pdb VnD [296] http://vandd.org SuperCYP [297] http://bioinformatics.charite.de/supercyp genetic variants and drug response PharmGKB [298] http://www.pharmgkb.com association [294]. SNP and copy number annotation database (SCAN) annotates SNPs according to physical chromosomal location or effect on gene expression [293].…”

Identification of Low‐Molecular‐Weight Compounds Inhibiting Growth of Corynebacteria: Potential Lead Compounds for Antibiotics

“…The STRING [14] database indicates relationships with primarily hypothetical proteins, however a gene encoding a dGTP hydrolase and a gene encoding a histone N-acetyltransferase are loosely associated with CG2496(41-180). Furthermore, a comparison of the CG2496(41-180)-methiothepin binding site to a database of protein-ligand binding sites using CPASS [15] did not result in any hits above a 30% similarity threshold, which is the minimum score used to consider two proteins to have structurally and functionally similar binding sites. [15b] …”

“…Furthermore, a comparison of the CG2496(41-180)-methiothepin binding site to a database of protein-ligand binding sites using CPASS [15] did not result in any hits above a 30% similarity threshold, which is the minimum score used to consider two proteins to have structurally and functionally similar binding sites. [15b] …”