title: Predicting protein-DNA interactions by full search computational docking.
abstract: Protein-DNA interactions are essential for many biological processes. X-ray crystallography can provide high-resolution structures, but protein-DNA complexes are difficult to crystallize and typically contain only small DNA fragments. Thus, there is a need for computational methods that can provide useful predictions to give insights into mechanisms and guide the design of new experiments. We used the program DOT, which performs an exhaustive, rigid-body search between two macromolecules, to investigate four diverse protein-DNA interactions. Here, we compare our computational results with subsequent experimental data on related systems. In all cases, the experimental data strongly supported our structural hypotheses from the docking calculations: a mechanism for weak, nonsequence-specific DNA binding by a transcription factor, a large DNA-binding footprint on the surface of the DNA-repair enzyme uracil-DNA glycosylase (UNG), viral and host DNA-binding sites on the catalytic domain of HIV integrase, and a three-DNA-contact model of the linker histone bound to the nucleosome. In the case of UNG, the experimental design was based on the DNA-binding surface found by docking, rather than the much smaller surface observed in the crystallographic structure. These comparisons demonstrate that the DOT electrostatic energy gives a good representation of the distinctive electrostatic properties of DNA and DNA-binding proteins. The large, favourably ranked clusters resulting from the dockings identify active sites, map out large DNA-binding sites, and reveal multiple DNA contacts with a protein. Thus, computational docking can not only help to identify protein-DNA interactions in the absence of a crystal structure, but also expand structural understanding beyond known crystallographic structures.
authors: San Diego Supercomputer Center, University of California, San Diego, La Jolla, California, 92093.
authors: Victoria A
authors: VA
authors: Roberts
authors: Michael E
authors: ME
authors: Pique
authors: Lynn F
authors: LF
authors: Ten Eyck
authors: Sheng
authors: S
authors: Li
mesh_terms: D000465:Algorithms; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000737:chemistry*; D019427:HIV Integrase / Q000737:chemistry*; D006657:Histones / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D011485:Protein Binding; D013816:Thermodynamics; D051981:Uracil-DNA Glycosidase / Q000737:chemistry*
chemical_list: D004268:DNA-Binding Proteins; D006657:Histones; D004247:DNA; D019427:HIV Integrase; D051981:Uracil-DNA Glycosidase
keywords: HIV integrase; Poisson-Boltzmann electrostatics; hydrogen/deuterium exchange; linker histone; protein-DNA structure; transcription factor; uracil-DNA glycosylase
references: Structure. 1996 Dec 15;4(12):1381-5
references: 8994964
references: Proc Natl Acad Sci U S A. 2010 May 25;107(21):9620-5
references: 20457934
references: Proteins. 2004 Oct 1;57(1):172-87
references: 15326602
references: Cell. 2008 May 30;133(5):789-800
references: 18510924
references: EMBO J. 1986 Dec 20;5(13):3531-7
references: 3104028
references: FEBS J. 2009 Jun;276(11):2926-46
references: 19490099
references: EMBO J. 1997 Nov 17;16(22):6849-59
references: 9362498
references: Nucleic Acids Res. 2006 Jul 04;34(11):3317-25
references: 16820531
references: Nature. 2007 Sep 27;449(7161):433-7
references: 17704764
references: EMBO J. 1998 Sep 1;17(17):5214-26
references: 9724657
references: Proc Natl Acad Sci U S A. 2000 May 9;97(10):5083-8
references: 10805771
references: J Med Chem. 2004 Feb 12;47(4):821-8
references: 14761184
references: Cell. 2000 Oct 27;103(3):449-56
references: 11081631
references: Nature. 1996 Nov 7;384(6604):87-92
references: 8900285
references: Proteins. 2010 Nov 15;78(15):3197-204
references: 20607855
references: Proc Natl Acad Sci U S A. 1992 Mar 15;89(6):2195-9
references: 1549581
references: Biophys J. 1999 Sep;77(3):1191-205
references: 10465734
references: Biochemistry. 1995 Jan 10;34(1):128-38
references: 7819187
references: J Biol Chem. 1992 Apr 25;267(12):8685-91
references: 1569108
references: Bioinformatics. 2009 Oct 1;25(19):2544-51
references: 19620099
references: Nature. 2010 Nov 11;468(7321):326-9
references: 21068843
references: Cell. 2001 May 18;105(4):473-85
references: 11371344
references: Proteins. 2005 Aug 1;60(2):150-69
references: 15981261
references: J Struct Biol. 2006 Mar;153(3):278-83
references: 16427316
references: Proc Natl Acad Sci U S A. 2006 May 30;103(22):8384-9
references: 16717183
references: Proteins. 1997;Suppl 1:226-30
references: 9485517
references: J Mol Biol. 1999 Apr 16;287(5):877-96
references: 10222198
references: Trends Genet. 2010 Feb;26(2):75-83
references: 20074831
references: Biochemistry. 2008 Feb 12;47(6):1797-807
references: 18197706
references: J Mol Biol. 1994 Jan 7;235(1):318-24
references: 8289251
references: J Mol Biol. 2007 Nov 2;373(4):839-50
references: 17870091
references: Bioorg Med Chem Lett. 2005 Jan 17;15(2):475-7
references: 15603976
references: Proteins. 2002 Jun 1;47(4):409-43
references: 12001221
references: J Comput Chem. 2010 Jan 30;31(2):317-42
references: 19462412
references: EMBO J. 2000 Oct 2;19(19):5167-77
references: 11013219
references: J Chem Phys. 2005 Jun 1;122(21):214102
references: 15974723
references: J Biol Chem. 1999 Dec 31;274(53):38051-60
references: 10608874
references: J Comput Chem. 2013 Jul 30;34(20):1743-58
references: 23695987
references: Proteins. 2003 Jul 1;52(1):80-7
references: 12784371
references: Nucleic Acids Res. 2011 Nov;39(21):9139-54
references: 21835779
references: Biochem Biophys Res Commun. 2003 Oct 31;310(4):1083-8
references: 14559226
references: Nucleic Acids Res. 2009 Jul;37(Web Server issue):W235-9
references: 19417072
references: Nucleic Acids Res. 2011 Nov 1;39(20):e135
references: 21835777
references: Proteins. 2006 Nov 1;65(2):392-406
references: 16933295
references: Cell. 2008 Oct 3;135(1):97-109
references: 18854158
references: EMBO J. 1990 May;9(5):1651-8
references: 2328730
references: Proteins. 2003 Jul 1;52(1):2-9
references: 12784359
references: Nucleic Acids Res. 2012 Jul;40(13):6070-81
references: 22492624
references: EMBO J. 2001 Apr 17;20(8):2041-50
references: 11296236
references: J Biol Chem. 2001 May 18;276(20):17373-9
references: 11279025
references: J Mol Biol. 1992 Feb 5;223(3):651-9
references: 1542112
references: Proc Natl Acad Sci U S A. 2001 Aug 28;98(18):10037-41
references: 11517324
references: Nature. 1993 Mar 18;362(6417):219-23
references: 8384699
references: Proteins. 1994 Dec;20(4):320-9
references: 7731951
references: Nature. 1998 Sep 24;395(6700):402-5
references: 9759733
references: Protein Sci. 2002 Mar;11(3):571-87
references: 11847280
references: J Mol Biol. 2000 Apr 7;297(4):947-59
references: 10736229
references: J Mol Biol. 2000 Nov 17;304(1):21-33
references: 11071807
references: Nature. 2010 Mar 11;464(7286):232-6
references: 20118915
references: Pharmacol Ther. 2000 Mar;85(3):123-31
references: 10739867
references: Science. 2004 Jul 16;305(5682):386-9
references: 15256668
references: J Mol Biol. 1997 Sep 12;272(1):106-20
references: 9299341
references: Protein Eng. 1994 Jun;7(6):761-7
references: 7937706
references: Proteins. 2003 Jul 1;52(1):51-67
references: 12784368
references: Biophys J. 1999 Jun;76(6):2999-3011
references: 10354426
references: J Mol Biol. 1990 Jan 20;211(2):479-91
references: 2106584
references: Nat Struct Mol Biol. 2009 Nov;16(11):1118-20
references: 19888307
references: Acc Chem Res. 2002 Jun;35(6):350-7
references: 12069619
references: EMBO J. 1999 Jul 1;18(13):3834-44
references: 10393198
references: J Biol Chem. 1997 Mar 7;272(10):6561-6
references: 9045683
references: Protein Eng. 1989 Aug;2(8):577-82
references: 2682606
references: Protein Eng. 2001 Feb;14(2):105-13
references: 11297668
references: Proc Natl Acad Sci U S A. 1994 Aug 2;91(16):7817-21
references: 8052665
references: Nucleic Acids Res. 2010 Sep;38(17):5634-47
references: 20466807
references: Nat Struct Biol. 1998 Dec;5(12):1025-8
references: 9846868
references: BMC Bioinformatics. 2011 Jan 27;12:36
references: 21269517
references: Nature. 2005 Jul 7;436(7047):138-41
references: 16001076
references: Proteins. 1996 Aug;25(4):486-500
references: 8865343
references: Nature. 1997 Sep 18;389(6648):251-60
references: 9305837
references: Proteins. 2000 May 1;39(2):178-94
references: 10737939
references: Proteins. 1998 Dec 1;33(4):535-49
references: 9849937
references: IEEE/ACM Trans Comput Biol Bioinform. 2011 Jan-Mar;8(1):45-58
references: 21071796
references: EMBO J. 1988 Dec 1;7(12):3685-91
references: 3208745
references: Nucleic Acids Res. 2003 Dec 15;31(24):7189-98
references: 14654694
references: Biochem J. 1997 Jul 1;325 ( Pt 1):1-16
references: 9224623
references: Prog Lipid Res. 1999 Mar;38(2):129-97
references: 10396600
references: Biochemistry. 1978 Dec 12;17(25):5524-31
references: 728412
references: Biochemistry. 1999 Feb 16;38(7):1999-2017
references: 10026283
references: Proc Natl Acad Sci U S A. 2007 Mar 20;104(12):5008-13
references: 17360341
references: Nat Struct Mol Biol. 2004 Dec;11(12):1230-6
references: 15558051
references: Biochemistry. 2010 Jun 22;49(24):4957-67
references: 20469926