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


RESULTS
We 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.


CONCLUSIONS
CPASS 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.
Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE 68588-0304 USA. rpowers3@unl.edu.
Robert
R
Powers
Jennifer C
JC
Copeland
Jaime L
JL
Stark
Adam
A
Caprez
Ashu
A
Guru
David
D
Swanson
Nucleic Acids Res. 2010 Jul;38(Web Server issue):W469-73
20513649
Comb Chem High Throughput Screen. 2007 Sep;10(8):676-97
18045080
Nucleic Acids Res. 2004 Jan 1;32(Database issue):D431-3
14681450
Nucleic Acids Res. 2006 Jul 11;34(11):3309-16
16835308
Protein Eng. 1999 Feb;12(2):85-94
10195279
Curr Opin Struct Biol. 2005 Jun;15(3):275-84
15963890
J Mol Biol. 2001 Mar 23;307(2):721-35
11254392
Nucleic Acids Res. 2007 Jan;35(Database issue):D291-7
17135200
PLoS One. 2009 Oct 13;4(10):e7442
19823588
J Mol Biol. 1999 Apr 23;288(1):147-64
10329133
Proteins. 2006 Mar 15;62(3):587-603
16374783
BMC Bioinformatics. 2007 Aug 08;8:294
17686158
Nucleic Acids Res. 2009 Jul;37(Web Server issue):W485-91
19443448
Bioinformatics. 2000 Jul;16(7):658-9
11038339
Proc Natl Acad Sci U S A. 1992 Nov 15;89(22):10915-9
1438297
Comput Appl Biosci. 1993 Dec;9(6):745-56
8143162
Drug Discov Today. 2008 Feb;13(3-4):172-9
18275915
J Mol Biol. 2005 Mar 4;346(4):1173-88
15701525
BMC Bioinformatics. 2003 Sep 11;4:41
12969510
Bioinformatics. 2007 Aug 15;23(16):2180-2
17545180
Genome Biol. 2000;1(5):REVIEWS0005
11178260
J Comput Chem. 2004 Oct;25(13):1605-12
15264254
J Am Chem Soc. 2006 Nov 29;128(47):15292-9
17117882
Database (Oxford). 2010 Jul 06;2010:baq011
20624718
Nucleic Acids Res. 2000 Jan 1;28(1):257-9
10592240
Protein Sci. 2009 Mar;18(3):606-18
19241370
Nucleic Acids Res. 2007 Jul;35(Web Server issue):W398-402
17567616
Nucleic Acids Res. 2000 Jan 1;28(1):235-42
10592235
Biochem Mol Biol Educ. 2006 Jul;34(4):255-61
21638687
Proteins. 2008 May 1;71(2):960-71
18004762
BMC Bioinformatics. 2005 Dec 01;6 Suppl 4:S5
16351754
Proc Natl Acad Sci U S A. 2009 Oct 13;106(41):17377-82
19805138
Proteins. 2006 Oct 1;65(1):124-35
16862592
Nucleic Acids Res. 2003 Jul 1;31(13):3341-4
12824322
Nucleic Acids Res. 2004 Jul 1;32(Web Server issue):W76-82
15215355
Proteins. 2010 Dec;78(16):3328-40
20818668
J Mol Biol. 2003 Mar 7;326(5):1307-16
12595245
Nucleic Acids Res. 2010 Jan;38(Database issue):D190-5
19900971
J Mol Biol. 1987 Jun 20;195(4):957-61
3656439
Nucleic Acids Res. 2005 Jul 1;33(Web Server issue):W89-93
15980588
Proteins. 1993 Sep;17(1):49-61
8234244
Nucleic Acids Res. 2007 Jul;35(Web Server issue):W573-7
17584799
J Chem Inf Model. 2006 Mar-Apr;46(2):736-42
16563004
Brief Bioinform. 2006 Sep;7(3):225-42
16772267