title: A critical evaluation of in silico methods for detection of membrane protein intrinsic disorder.
abstract: Intrinsically disordered regions in proteins possess important biological roles including transcriptional regulation, molecular recognition, and provision of sites for posttranslational modification. In three-dimensional crystallization of both soluble and membrane proteins, identification and removal of disordered regions is often necessary for obtaining crystals possessing sufficient long-range order for structure determination. Disordered regions can be identified experimentally, with techniques such as limited proteolysis coupled with mass spectrometry, or computationally, by using disorder prediction programs, of which many are available. Although these programs use various methods to predict disorder from a protein's primary sequence, they all were developed using information derived from soluble protein structures. Therefore, their performance and accuracy when applied to integral membrane proteins remained an open question. We evaluated the performance of 13 disorder prediction programs on a dataset containing 343 membrane proteins, and upon subdatasets containing only α-helical or β-barrel proteins. These programs were ranked using multiple metrics, including metrics specifically created for membrane proteins. Analysis of these data shows a clear distinction between programs that accurately predict disordered regions in membrane proteins and programs which perform poorly, and allows for the robust integration of in silico disorder prediction into our PSI:Biology membrane protein structural genomics pipeline.
authors.affiliation: Department of Molecular Physiology and Biological Physics, Center for Membrane Biology, University of Virginia, Charlottesville, Virginia.
authors.forename: Edward E
authors.initials: EE
authors.lastname: Pryor
authors.affiliation: Department of Molecular Physiology and Biological Physics, Center for Membrane Biology, University of Virginia, Charlottesville, Virginia. Electronic address: mwiener@virginia.edu.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Wiener
mesh_terms: D019540:Area Under Curve; D019295:Computational Biology / Q000379:methods*; D003198:Computer Simulation; D003460:Crystallization; D030562:Databases, Protein; D064267:Intrinsically Disordered Proteins / Q000737:chemistry*; D008565:Membrane Proteins / Q000737:chemistry*; D017433:Protein Structure, Secondary; D012995:Solubility
chemical_list: D064267:Intrinsically Disordered Proteins; D008565:Membrane Proteins
references.citation: Nat Rev Mol Cell Biol. 2005 Mar;6(3):197-208
references.pmid: 15738986
references.citation: Proteins. 2003;53 Suppl 6:566-72
references.pmid: 14579347
references.citation: J Recept Signal Transduct Res. 2010 Oct;30(5):331-6
references.pmid: 20836733
references.citation: J Bioinform Comput Biol. 2005 Feb;3(1):35-60
references.pmid: 15751111
references.citation: Biochim Biophys Acta. 2013 Jun;1834(6):1202-9
references.pmid: 23099262
references.citation: Bioinformatics. 2009 Feb 15;25(4):451-7
references.pmid: 19164304
references.citation: Nucleic Acids Res. 2008 Jul 1;36(Web Server issue):W190-6
references.pmid: 18385152
references.citation: J Mol Graph Model. 2001;19(1):26-59
references.pmid: 11381529
references.citation: Structure. 2003 Nov;11(11):1453-9
references.pmid: 14604535
references.citation: Pac Symp Biocomput. 2012;:94-103
references.pmid: 22174266
references.citation: Mol Biosyst. 2012 Jan;8(1):320-6
references.pmid: 22012032
references.citation: Nature. 2011 Jan 13;469(7329):236-40
references.pmid: 21228876
references.citation: Nat Rev Mol Cell Biol. 2006 Dec;7(12):909-18
references.pmid: 17139331
references.citation: J Struct Funct Genomics. 2009 Dec;10(4):255-68
references.pmid: 19859826
references.citation: Acta Crystallogr D Biol Crystallogr. 2006 Oct;62(Pt 10):1260-6
references.pmid: 17001103
references.citation: Proteins. 2003;53 Suppl 6:561-5
references.pmid: 14579346
references.citation: BMC Genomics. 2009 Jul 07;10 Suppl 1:S7
references.pmid: 19594884
references.citation: Mol Biosyst. 2012 Jan;8(1):114-21
references.pmid: 21874190
references.citation: Proteins. 2011;79 Suppl 10:107-18
references.pmid: 21928402
references.citation: Biochim Biophys Acta. 1975 Oct 20;405(2):442-51
references.pmid: 1180967
references.citation: Adv Protein Chem. 2002;62:311-40
references.pmid: 12418108
references.citation: J Mol Biol. 2004 Mar 26;337(3):635-45
references.pmid: 15019783
references.citation: Nucleic Acids Res. 2000 Jan 1;28(1):235-42
references.pmid: 10592235
references.citation: BMC Genomics. 2008;9 Suppl 1:S7
references.pmid: 18366620
references.citation: J Struct Biol. 2012 Oct;180(1):201-15
references.pmid: 22651963
references.citation: Proteins. 2009;77 Suppl 9:210-6
references.pmid: 19774619
references.citation: J Biomol Struct Dyn. 2012;29(4):799-813
references.pmid: 22208280
references.citation: Fold Des. 1997;2(2):R17-26
references.pmid: 9135978
references.citation: Biochim Biophys Acta. 1998 Feb 17;1382(2):191-206
references.pmid: 9540791
references.citation: Proteins. 2007;69 Suppl 8:129-36
references.pmid: 17680688
references.citation: J Mol Biol. 2005 Aug 12;351(2):431-42
references.pmid: 16005885
references.citation: Mol Biosyst. 2009 Dec;5(12):1688-1702
references.pmid: 19585006
references.citation: Bioinformatics. 2006 Jul 1;22(13):1546-50
references.pmid: 16601002
references.citation: Methods. 2011 Sep;55(1):3-11
references.pmid: 21906678
references.citation: Science. 2007 Nov 23;318(5854):1258-65
references.pmid: 17962520
references.citation: Annu Rev Biophys Biomol Struct. 1999;28:319-65
references.pmid: 10410805
references.citation: J Mol Biol. 2002 Oct 25;323(3):573-84
references.pmid: 12381310
references.citation: Science. 2007 Nov 23;318(5854):1266-73
references.pmid: 17962519
references.citation: Science. 2012 Sep 21;337(6101):1460-1
references.pmid: 22997313
references.citation: Proteins. 2001 Jan 1;42(1):38-48
references.pmid: 11093259
references.citation: Bioinformatics. 2005 Aug 15;21(16):3433-4
references.pmid: 15955779
references.citation: Nucleic Acids Res. 2004 Feb 11;32(3):1037-49
references.pmid: 14960716
references.citation: Stat Med. 2000 May 15;19(9):1141-64
references.pmid: 10797513
references.citation: Proteins. 2005;61 Suppl 7:167-75
references.pmid: 16187359
references.citation: Bioinformatics. 2005 Aug 15;21(16):3435-8
references.pmid: 15955783
references.citation: Mol Biosyst. 2012 Jan;8(1):97-104
references.pmid: 21874205
references.citation: Radiology. 1982 Apr;143(1):29-36
references.pmid: 7063747
references.citation: Proteins. 2006 Jan 1;62(1):24-45
references.pmid: 16287116
references.citation: Annu Rev Biophys Biomol Struct. 2001;30:67-85
references.pmid: 11340052
references.citation: J Mol Biol. 2006 May 19;358(5):1221-8
references.pmid: 16574146
references.citation: BMC Bioinformatics. 2006 Apr 17;7:208
references.pmid: 16618368
references.citation: Bioinformatics. 2005 Aug 15;21(16):3369-76
references.pmid: 15947016
references.citation: Methods Mol Biol. 2012;866:75-86
references.pmid: 22454116
references.citation: Methods. 2004 Nov;34(3):364-72
references.pmid: 15325654
references.citation: Nucleic Acids Res. 2005 Jan 1;33(Database issue):D275-8
references.pmid: 15608195
references.citation: Nucleic Acids Res. 2003 Jul 1;31(13):3701-8
references.pmid: 12824398
references.citation: BMC Bioinformatics. 2009 Dec 21;10:436
references.pmid: 20025768
references.citation: Biochim Biophys Acta. 2013 Feb;1834(2):487-98
references.pmid: 23232152
references.citation: Bioinformatics. 2012 Feb 15;28(4):503-9
references.pmid: 22190692