INTREPID--INformation-theoretic TREe traversal for Protein functional site IDentification.
BACKGROUND
Identification of functionally important residues in proteins plays a significant role in biological discovery. Here, we present INTREPID--an information-theoretic approach for functional site identification that exploits the information in large diverse multiple sequence alignments (MSAs). INTREPID uses a traversal of the phylogeny in combination with a positional conservation score, based on Jensen-Shannon divergence, to rank positions in an MSA. While knowledge of protein 3D structure can significantly improve the accuracy of functional site identification, since structural information is not available for a majority of proteins, INTREPID relies solely on sequence information. We evaluated INTREPID on two tasks: predicting catalytic residues and predicting specificity determinants.


RESULTS
In catalytic residue prediction, INTREPID provides significant improvements over Evolutionary Trace, ConSurf as well as over a baseline global conservation method on a set of 100 manually curated enzymes from the Catalytic Site Atlas. In particular, INTREPID is able to better predict catalytic positions that are not globally conserved and hence, attains improved sensitivity at high values of specificity. We also investigated the performance of INTREPID as a function of the evolutionary divergence of the protein family. We found that INTREPID is better able to exploit the diversity in such families and that accuracy improves when homologs with very low sequence identity are included in an alignment. In specificity determinant prediction, when subtype information is known, INTREPID-SPEC, a variant of INTREPID, attains accuracies that are competitive with other approaches for this task.


BACKGROUND
INTREPID is available for 16919 families in the PhyloFacts resource (http://phylogenomics.berkeley.edu/phylofacts).
Sankararaman
Sriram
S
Department of Electrical Engineering & Computer Science and Department of Bioengineering, University of California, Berkeley, USA. sriram_s@cs.berkeley.edu
Sjölander
Kimmen
K
D000465:Algorithms; D001665:Binding Sites; D030562:Databases, Protein; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry* / Q000235:genetics; D016415:Sequence Alignment; D020539:Sequence Analysis, Protein; D012984:Software
D011506:Proteins
Bioinformatics. 2008 Jul 1;24(13):1473-80
18450811
J Mol Biol. 2003 Jul 18;330(4):719-34
12850142
Bioorg Med Chem. 2006 Oct 1;14(19):6486-91
16828555
J Mol Biol. 2001 Apr 6;307(4):1113-43
11286560
J Mol Biol. 2001 Sep 28;312(4):885-96
11575940
EMBO J. 2000 Sep 15;19(18):5019-26
10990465
Nat Struct Biol. 1995 Feb;2(2):171-8
7749921
Protein Sci. 2007 Feb;16(2):216-26
17189479
Protein Sci. 2004 Apr;13(4):884-92
15010543
Bioinformatics. 2007 Aug 1;23(15):1875-82
17519246
Bioinformatics. 2002;18 Suppl 1:S71-7
12169533
Proc Natl Acad Sci U S A. 1992 Nov 15;89(22):10915-9
1438297
J Mol Biol. 2004 Mar 5;336(5):1265-82
15037084
Protein Sci. 2007 Jul;16(7):1316-28
17586768
Proteins. 1991;11(4):297-313
1758884
Nucleic Acids Res. 2000 Jan 1;28(1):254-6
10592239
J Mol Biol. 1996 Feb 16;256(1):201-13
8609611
J Mol Biol. 2003 Feb 28;326(4):1289-302
12589769
J Mol Biol. 2000 Oct 13;303(1):61-76
11021970
J Mol Biol. 2002 Aug 2;321(1):7-20
12139929
BMC Bioinformatics. 2006 Aug 17;7:385
16916457
Nucleic Acids Res. 2004 Jan 1;32(Database issue):D129-33
14681376
Trends Biochem Sci. 2002 Aug;27(8):419-26
12151227
J Mol Biol. 2001 Apr 13;307(5):1487-502
11292355
Nucleic Acids Res. 2005 Jul 1;33(Web Server issue):W299-302
15980475
Proc Natl Acad Sci U S A. 2001 Oct 23;98(22):12473-8
11606719
Mol Biol Evol. 2004 Sep;21(9):1781-91
15201400
Protein Sci. 2004 Feb;13(2):443-56
14739328
Bioinformatics. 2005 May 1;21(9):1908-16
15701681
J Mol Biol. 2001 Aug 10;311(2):395-408
11478868
Proteins. 1991;9(1):56-68
2017436
J Mol Biol. 1996 Mar 29;257(2):342-58
8609628
Nucleic Acids Res. 2004 Jan 1;32(Database issue):D115-9
14681372
BMC Bioinformatics. 2006 Jun 21;7:312
16790052
Proteins. 2006 Feb 1;62(2):479-88
16304646
Nucleic Acids Res. 1997 Sep 1;25(17):3389-402
9254694
Nucleic Acids Res. 2006;34(22):6540-8
17130172
Bioinformatics. 2006 Jan 15;22(2):164-71
16278237
Bioinformatics. 2005 Jun;21 Suppl 1:i258-65
15961465
Bioinformatics. 2005 Jun 1;21(11):2629-35
15797914
Bioinformatics. 2005 Jun;21 Suppl 1:i328-37
15961475
Nucleic Acids Res. 2004 Mar 19;32(5):1792-7
15034147