title: Predicting flexible loop regions that interact with ligands: the challenge of accurate scoring.
abstract: Flexible loop regions play a critical role in the biological function of many proteins and have been shown to be involved in ligand binding. In the context of structure-based drug design, using or predicting an incorrect loop configuration can be detrimental to the study if the loop is capable of interacting with the ligand. Three protein systems, each with at least one flexible loop region in close proximity to the known binding site, were selected for loop prediction using the CorLps program; a six residue loop region from phosphoribosylglycinamide formyltransferase (GART), two nine residue loop regions from cytochrome P450 (CYP) 119, and an 11 residue loop region from enolase were selected for loop prediction. The results of this study indicate that the statistically based DFIRE scoring function implemented in the CorLps program did not accurately rank native-like predicted loop configurations in any protein system. In an attempt to improve the ranking of the native-like predicted loop configurations, the MM/GBSA and the optimized MM/GBSA-dsr scoring functions were used to re-rank the predicted loops with and without bound ligand. In general, single snapshot MM/GBSA scoring provided the best ranking of native-like loop configurations. Based on the scoring function analyses presented, the optimal ranking of native-like loop configurations is still a difficult challenge and the choice of the "best" scoring function appears to be system dependent.
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Danielson
authors.forename: Markus A
authors.initials: MA
authors.lastname: Lill
mesh_terms: D020816:Amino Acid Motifs; D019843:Archaeal Proteins / Q000737:chemistry; D003198:Computer Simulation; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry; D029968:Escherichia coli Proteins / Q000737:chemistry; D006860:Hydrogen Bonding; D008958:Models, Molecular; D010751:Phosphopyruvate Hydratase / Q000737:chemistry; D051026:Phosphoribosylglycinamide Formyltransferase / Q000737:chemistry; D011485:Protein Binding; D017433:Protein Structure, Secondary; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry; D012984:Software; D013816:Thermodynamics
chemical_list: D019843:Archaeal Proteins; D029968:Escherichia coli Proteins; D029701:Saccharomyces cerevisiae Proteins; D003577:Cytochrome P-450 Enzyme System; C408874:CYP119 protein, Sulfolobus solfataricus; D051026:Phosphoribosylglycinamide Formyltransferase; D010751:Phosphopyruvate Hydratase
references.citation: Chembiochem. 2004 Feb 6;5(2):224-30
references.pmid: 14760744
references.citation: J Phys Chem B. 2006 Nov 30;110(47):24121-37
references.pmid: 17125384
references.citation: Protein Eng. 1999 Sep;12(9):713-20
references.pmid: 10506280
references.citation: Proteins. 2008 Feb 15;70(3):834-43
references.pmid: 17729286
references.citation: Protein Sci. 2002 Nov;11(11):2714-26
references.pmid: 12381853
references.citation: Nucleic Acids Res. 2010 Jan;38(Database issue):D142-8
references.pmid: 19843607
references.citation: Biophys J. 2008 Apr 15;94(8):3227-40
references.pmid: 18178653
references.citation: Mol Endocrinol. 2000 Aug;14(8):1210-21
references.pmid: 10935545
references.citation: Proteins. 2011 Feb;79(2):477-98
references.pmid: 21069716
references.citation: J Med Chem. 2008 Dec 25;51(24):7921-32
references.pmid: 19053777
references.citation: J Biol Chem. 2007 Apr 6;282(14):10387-97
references.pmid: 17293349
references.citation: J Biol Chem. 2002 Apr 26;277(17):14724-30
references.pmid: 11854276
references.citation: J Mol Biol. 1999 Jan 29;285(4):1735-47
references.pmid: 9917408
references.citation: J Phys Chem B. 2009 Feb 12;113(6):1662-72
references.pmid: 19159290
references.citation: Proteins. 2006 Mar 1;62(4):956-69
references.pmid: 16372349
references.citation: J Comput Chem. 2005 Dec;26(16):1668-88
references.pmid: 16200636
references.citation: J Biol Chem. 1997 May 23;272(21):13475-8
references.pmid: 9153190
references.citation: Annu Rev Biophys Biomol Struct. 2000;29:291-325
references.pmid: 10940251
references.citation: Proteins. 2010 May 15;78(7):1705-23
references.pmid: 20186976
references.citation: Proc Natl Acad Sci U S A. 2004 Jan 13;101(2):440-5
references.pmid: 14704269
references.citation: Biochemistry. 1995 Apr 4;34(13):4325-30
references.pmid: 7703246
references.citation: J Mol Biol. 2001 Aug 10;311(2):421-30
references.pmid: 11478870
references.citation: J Phys Chem B. 2006 Jun 29;110(25):12796-808
references.pmid: 16800615
references.citation: Proteins. 2008 Apr;71(1):153-64
references.pmid: 17932934
references.citation: Mol Pharmacol. 2000 Feb;57(2):213-8
references.pmid: 10648630
references.citation: J Mol Endocrinol. 2000 Jun;24(3):353-64
references.pmid: 10828828
references.citation: Biochemistry. 2009 Jun 2;48(21):4548-56
references.pmid: 19348462
references.citation: Biochim Biophys Acta. 2009 Aug;1794(8):1159-67
references.pmid: 19332152
references.citation: Protein Sci. 2004 Feb;13(2):391-9
references.pmid: 14739324
references.citation: Mol Pharmacol. 2009 Oct;76(4):833-42
references.pmid: 19643997
references.citation: Nucleic Acids Res. 2000 Jan 1;28(1):235-42
references.pmid: 10592235
references.citation: Chembiochem. 2001 May 4;2(5):355-63
references.pmid: 11828464
references.citation: J Mol Biol. 2007 Oct 12;373(1):96-111
references.pmid: 17765263
references.citation: Proc Natl Acad Sci U S A. 1992 Jul 1;89(13):6114-8
references.pmid: 1631098
references.citation: Annu Rev Pharmacol Toxicol. 2002;42:437-67
references.pmid: 11807179
references.citation: J Am Chem Soc. 2005 Jul 6;127(26):9632-40
references.pmid: 15984891
references.citation: J Biol Chem. 2002 Nov 8;277(45):43301-8
references.pmid: 12196517
references.citation: J Med Chem. 2006 Nov 2;49(22):6596-606
references.pmid: 17064078
references.citation: Biochemistry. 1994 Aug 9;33(31):9333-42
references.pmid: 8049235
references.citation: J Inorg Biochem. 2002 Sep 20;91(4):491-501
references.pmid: 12237217
references.citation: J Chem Theory Comput. 2007 Jan 1;3(1):156-169
references.pmid: 21072141
references.citation: Nat Methods. 2009 Aug;6(8):551-2
references.pmid: 19644455
references.citation: Proteins. 2010 May 15;78(7):1748-59
references.pmid: 20186974
references.citation: Proc Natl Acad Sci U S A. 1958 Feb;44(2):98-104
references.pmid: 16590179
references.citation: Genome Res. 1999 Nov;9(11):1106-15
references.pmid: 10568750
references.citation: J Biol Chem. 2000 Oct 6;275(40):31086-92
references.pmid: 10859321
references.citation: J Chem Theory Comput. 2010;6(4):1018-1027
references.pmid: 20467461
references.citation: J Comput Chem. 2010 Mar;31(4):797-810
references.pmid: 19569205
references.citation: Protein Eng. 1993 Apr;6(3):297-303
references.pmid: 8506264
references.citation: J Biol Chem. 2009 Oct 2;284(40):27370-6
references.pmid: 19643731
references.citation: Biochemistry. 2011 Jul 19;50(28):6157-69
references.pmid: 21678954
references.citation: Life Sci. 2009 Aug 12;85(7-8):303-8
references.pmid: 19555696
references.citation: J Biol Chem. 1999 Nov 5;274(45):32055-62
references.pmid: 10542238
references.citation: FEBS Lett. 1999 Feb 19;445(1):23-6
references.pmid: 10069367
references.citation: J Biol Chem. 2006 Oct 6;281(40):30132-42
references.pmid: 16893894
references.citation: J Mol Biol. 1992 Sep 5;227(1):283-92
references.pmid: 1522592