title: Biological insights from topology independent comparison of protein 3D structures.
abstract: Comparing and classifying the three-dimensional (3D) structures of proteins is of crucial importance to molecular biology, from helping to determine the function of a protein to determining its evolutionary relationships. Traditionally, 3D structures are classified into groups of families that closely resemble the grouping according to their primary sequence. However, significant structural similarities exist at multiple levels between proteins that belong to these different structural families. In this study, we propose a new algorithm, CLICK, to capture such similarities. The method optimally superimposes a pair of protein structures independent of topology. Amino acid residues are represented by the Cartesian coordinates of a representative point (usually the C(α) atom), side chain solvent accessibility, and secondary structure. Structural comparison is effected by matching cliques of points. CLICK was extensively benchmarked for alignment accuracy on four different sets: (i) 9537 pair-wise alignments between two structures with the same topology; (ii) 64 alignments from set (i) that were considered to constitute difficult alignment cases; (iii) 199 pair-wise alignments between proteins with similar structure but different topology; and (iv) 1275 pair-wise alignments of RNA structures. The accuracy of CLICK alignments was measured by the average structure overlap score and compared with other alignment methods, including HOMSTRAD, MUSTANG, Geometric Hashing, SALIGN, DALI, GANGSTA(+), FATCAT, ARTS and SARA. On average, CLICK produces pair-wise alignments that are either comparable or statistically significantly more accurate than all of these other methods. We have used CLICK to uncover relationships between (previously) unrelated proteins. These new biological insights include: (i) detecting hinge regions in proteins where domain or sub-domains show flexibility; (ii) discovering similar small molecule binding sites from proteins of different folds and (iii) discovering topological variants of known structural/sequence motifs. Our method can generally be applied to compare any pair of molecular structures represented in Cartesian coordinates as exemplified by the RNA structure superimposition benchmark.
authors: Bioinformatics Institute, 30 Biopolis Street, #07-01 Matrix, Singapore 138671.
authors: Minh N
authors: MN
authors: Nguyen
authors: M S
authors: MS
authors: Madhusudhan
references: J Mol Biol. 1995 Apr 7;247(4):536-40
references: 7723011
references: Protein Eng. 2002 Oct;15(10):783-98
references: 12468712
references: Bioinformatics. 2008 Dec 1;24(23):2780-1
references: 18818215
references: J Mol Biol. 1978 Mar 15;119(4):537-55
references: 642001
references: J Mol Biol. 1996 Jul 26;260(4):604-20
references: 8759323
references: J Mol Biol. 1980 Jan 25;136(3):225-70
references: 7373651
references: J Mol Biol. 1988 Sep 5;203(1):251-68
references: 3184190
references: Bioinformatics. 2008 Mar 1;24(5):645-51
references: 18175768
references: Biochemistry. 2000 Mar 14;39(10):2530-7
references: 10704202
references: Bioinformatics. 2007 Jan 15;23(2):e219-24
references: 17237095
references: Science. 1994 Jun 24;264(5167):1891-903
references: 7516580
references: Nat Struct Biol. 1996 Oct;3(10):834-7
references: 8836097
references: Nucleic Acids Res. 2007 Jan;35(Database issue):D253-9
references: 17068077
references: Structure. 2002 Mar;10(3):435-40
references: 12005441
references: J Mol Biol. 2008 Sep 5;381(3):785-802
references: 18620705
references: Bioinformatics. 2000 Jun;16(6):566-7
references: 10980157
references: Nucleic Acids Res. 2004 Jan 1;32(Database issue):D203-7
references: 14681395
references: Nucleic Acids Res. 2009 Jul;37(Web Server issue):W260-5
references: 19483098
references: Nature. 1960 Feb 13;185(4711):416-22
references: 18990801
references: J Mol Biol. 2005 Mar 4;346(4):1173-88
references: 15701525
references: FEBS Lett. 2007 Mar 6;581(5):935-8
references: 17303126
references: BMC Bioinformatics. 2008 Aug 31;9:358
references: 18759993
references: PLoS Comput Biol. 2009 Mar;5(3):e1000331
references: 19325884
references: J Comput Chem. 2004 Oct;25(13):1605-12
references: 15264254
references: Protein Sci. 2008 Aug;17(8):1374-82
references: 18583523
references: J Biol Chem. 2002 Jun 28;277(26):23898-908
references: 11953435
references: FEBS J. 2005 Jun;272(11):2800-10
references: 15943813
references: J Mol Biol. 1993 Dec 5;234(3):779-815
references: 8254673
references: Proc Natl Acad Sci U S A. 1991 Dec 1;88(23):10495-9
references: 1961713
references: Bioinformatics. 2003;19 Suppl 1:i95-104
references: 12855444
references: Bioinformatics. 2008 Aug 15;24(16):i112-8
references: 18689811
references: Nucleic Acids Res. 2003 Jul 15;31(14):3982-92
references: 12853614
references: Nucleic Acids Res. 2000 Jan 1;28(1):235-42
references: 10592235
references: Nucleic Acids Res. 2004 Jul 1;32(Web Server issue):W582-5
references: 15215455
references: J Struct Biol. 2001 May-Jun;134(2-3):167-85
references: 11551177
references: Nat Rev Mol Cell Biol. 2009 Mar;10(3):218-27
references: 19234479
references: Protein Sci. 2002 Nov;11(11):2606-21
references: 12381844
references: Bioinformatics. 2002 Jan;18(1):200-1
references: 11836232
references: J Mol Biol. 1990 Aug 5;214(3):765-79
references: 2388267
references: Nucleic Acids Res. 2007 Jan;35(Database issue):D317-21
references: 17065464
references: Protein Sci. 2002 Jun;11(6):1285-99
references: 12021428
references: Protein Eng. 1998 Sep;11(9):739-47
references: 9796821
references: Science. 1996 Aug 2;273(5275):595-603
references: 8662544
references: Nucleic Acids Res. 2009 Jan;37(Database issue):D310-4
references: 18996897
references: Bioinformatics. 2008 Aug 15;24(16):i98-104
references: 18689847
references: Bioinformatics. 2005 Sep 1;21 Suppl 2:ii47-53
references: 16204124
references: Protein Sci. 2004 Jul;13(7):1865-74
references: 15215530
references: BMC Struct Biol. 2007 Nov 16;7:78
references: 18005453
references: Biopolymers. 1983 Dec;22(12):2577-637
references: 6667333
references: Nucleic Acids Res. 2006 Jul 1;34(Web Server issue):W412-5
references: 16845038
references: Nucleic Acids Res. 1997 Sep 1;25(17):3389-402
references: 9254694
references: Nucleic Acids Res. 2008 Jan;36(Database issue):D419-25
references: 18000004
references: Proteins. 2006 Aug 15;64(3):559-74
references: 16736488
references: Nucleic Acids Res. 2007 Jul;35(Web Server issue):W393-7
references: 17478513
references: BMC Bioinformatics. 2007 May 22;8:167
references: 17519025
references: Protein Eng. 1993 Apr;6(3):279-88
references: 8506262
references: Structure. 1997 Aug 15;5(8):1093-108
references: 9309224
references: Protein Eng Des Sel. 2009 Sep;22(9):569-74
references: 19587024
references: Curr Opin Struct Biol. 2009 Jun;19(3):341-8
references: 19481444
references: Protein Sci. 2004 Apr;13(4):1043-55
references: 15044734
references: Curr Opin Struct Biol. 2001 Jun;11(3):348-53
references: 11406386
references: J Mol Biol. 1993 Sep 5;233(1):123-38
references: 8377180
references: Structure. 2006 Apr;14(4):757-66
references: 16615916