title: Computational and experimental studies of the interaction between phospho-peptides and the C-terminal domain of BRCA1.
abstract: The C-terminal domain of BRCA1(BRCT) is involved in the DNA repair pathway by recognizing the pSXXF motif in interacting proteins. It has been reported that short peptides containing this motif bind to BRCA1(BRCT) in the micromolar range with high specificity. In this work, the binding of pSXXF peptides has been studied computationally and experimentally in order to characterize their interaction with BRCA1(BRCT). Elucidation of the contacts that drive the protein-ligand interaction is critical for the development of high affinity small-molecule BRCA1 inhibitors. Molecular dynamics (MD) simulations revealed the key role of threonine at the peptide P+2 position in providing structural rigidity to the ligand in the bound state. The mutation at P+1 had minor effects. Peptide extension at the N-terminal position with the naphthyl amino acid exhibited a modest increase in binding affinity, what could be explained by the dispersion interaction of the naphthyl side-chain with a hydrophobic patch. Three in silico end-point methods were considered for the calculation of binding free energy. The Molecular Mechanics Poisson-Boltzmann Surface Area and the Solvated Interaction Energy methods gave reasonable agreement with experimental data, exhibiting a Pearlman predictive index of 0.71 and 0.78, respectively. The MM-quantum mechanics-surface area method yielded improved results, which was characterized by a Pearlman index of 0.78. The correlation coefficients were 0.59, 0.61 and 0.69, respectively. The ability to apply a QM level of theory within an end-point binding free energy protocol may provide a way for a consistent improvement of accuracy in computer-aided drug design.
authors.affiliation: School of Biomedical Informatics, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
authors.forename: Victor M
authors.initials: VM
authors.lastname: Anisimov
authors.forename: Arturas
authors.initials: A
authors.lastname: Ziemys
authors.forename: Smitha
authors.initials: S
authors.lastname: Kizhake
authors.forename: Ziyan
authors.initials: Z
authors.lastname: Yuan
authors.forename: Amarnath
authors.initials: A
authors.lastname: Natarajan
authors.forename: Claudio N
authors.initials: CN
authors.lastname: Cavasotto
mesh_terms: D020816:Amino Acid Motifs; D019313:BRCA1 Protein / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D006801:Humans; D056004:Molecular Dynamics Simulation; D009154:Mutation; D010748:Phosphopeptides / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013816:Thermodynamics
chemical_list: D019313:BRCA1 Protein; D010748:Phosphopeptides
references.citation: J Am Chem Soc. 2007 Sep 5;129(35):10658-9
references.pmid: 17685618
references.citation: J Phys Chem B. 2010 Oct 7;114(39):12666-78
references.pmid: 20839830
references.citation: Mol Cell Biol. 2008 Apr;28(8):2626-36
references.pmid: 18250151
references.citation: Nat Struct Mol Biol. 2007 Aug;14(8):710-5
references.pmid: 17643122
references.citation: J Comput Chem. 2004 Oct;25(13):1584-604
references.pmid: 15264253
references.citation: J Med Chem. 2005 Aug 25;48(17):5437-47
references.pmid: 16107143
references.citation: Biochemistry. 2005 Aug 23;44(33):10941-6
references.pmid: 16101277
references.citation: J Chem Theory Comput. 2005 May;1(3):484-93
references.pmid: 26641515
references.citation: Science. 2003 Oct 24;302(5645):639-42
references.pmid: 14576433
references.citation: J Med Chem. 2011 Jun 23;54(12):4264-8
references.pmid: 21574625
references.citation: Phys Chem Chem Phys. 2007 May 21;9(19):2362-70
references.pmid: 17492099
references.citation: Science. 2007 May 25;316(5828):1194-8
references.pmid: 17525340
references.citation: Phys Chem Chem Phys. 2010 Jan 14;12(2):307-22
references.pmid: 20023806
references.citation: Drug Discov Today. 2007 Sep;12(17-18):725-31
references.pmid: 17826685
references.citation: Curr Opin Struct Biol. 2004 Apr;14(2):217-24
references.pmid: 15093837
references.citation: Biophys J. 2006 Feb 1;90(3):864-77
references.pmid: 16284269
references.citation: Structure. 2010 Feb 10;18(2):167-76
references.pmid: 20159462
references.citation: J Mol Graph. 1996 Feb;14(1):33-8, 27-8
references.pmid: 8744570
references.citation: J Mol Biol. 2008 Jun 13;379(4):787-802
references.pmid: 18479705
references.citation: Philos Trans A Math Phys Eng Sci. 2005 Aug 15;363(1833):2037-53
references.pmid: 16099765
references.citation: J Mol Model. 2006 Feb;12(3):281-9
references.pmid: 16240095
references.citation: Nat Struct Mol Biol. 2004 Jun;11(6):519-25
references.pmid: 15133503
references.citation: Biophys J. 2004 Jan;86(1 Pt 1):67-74
references.pmid: 14695250
references.citation: J Comput Chem. 2005 Dec;26(16):1781-802
references.pmid: 16222654
references.citation: J Phys Chem B. 1998 Apr 30;102(18):3586-616
references.pmid: 24889800
references.citation: Mol Endocrinol. 2005 Sep;19(9):2273-82
references.pmid: 15919721
references.citation: Curr Top Med Chem. 2011;11(2):192-210
references.pmid: 20939788
references.citation: Chemphyschem. 2009 Dec 21;10(18):3194-6
references.pmid: 19830766
references.citation: J Comput Chem. 2009 Jul 30;30(10):1545-614
references.pmid: 19444816
references.citation: J Biol Chem. 2011 Feb 11;286(6):4292-301
references.pmid: 21127055
references.citation: Annu Rev Biophys Biophys Chem. 1989;18:431-92
references.pmid: 2660832
references.citation: Adv Protein Chem. 2003;66:27-85
references.pmid: 14631816
references.citation: Proteins. 2004 May 15;55(3):620-34
references.pmid: 15103626
references.citation: Methods Enzymol. 1991;202:497-511
references.pmid: 1784186
references.citation: J Phys Chem B. 2011 Jun 23;115(24):7896-905
references.pmid: 21585215
references.citation: Cell. 2001 Apr 6;105(1):149-60
references.pmid: 11301010
references.citation: Chembiochem. 2007 Sep 3;8(13):1585-91
references.pmid: 17691073
references.citation: Mol Cell. 2004 May 7;14(3):405-12
references.pmid: 15125843
references.citation: Nucleic Acids Res. 2008 Jan;36(Database issue):D360-7
references.pmid: 17962302
references.citation: Annu Rev Phys Chem. 2005;56:389-427
references.pmid: 15796706
references.citation: Proc Natl Acad Sci U S A. 1987 Oct;84(19):6611-5
references.pmid: 3477791
references.citation: J Med Chem. 2001 Oct 11;44(21):3417-23
references.pmid: 11585447
references.citation: J Phys Chem B. 2009 Apr 16;113(15):5290-300
references.pmid: 19320454
references.citation: Biochemistry. 2008 May 27;47(21):5767-73
references.pmid: 18452305
references.citation: J Phys Chem B. 2005 May 26;109(20):10474-83
references.pmid: 16852269
references.citation: J Chem Theory Comput. 2009 Jul 14;5(7):1749-60
references.pmid: 26610000
references.citation: Proteins. 2006 Nov 15;65(3):712-25
references.pmid: 16981200
references.citation: J Comput Chem. 2011 Jul 30;32(10):2254-63
references.pmid: 21484840
references.citation: Proc Natl Acad Sci U S A. 2005 May 10;102(19):6825-30
references.pmid: 15867154
references.citation: Structure. 2004 Jul;12(7):1137-46
references.pmid: 15242590
references.citation: Biopolymers. 2000-2001;56(4):275-91
references.pmid: 11754341
references.citation: J Med Chem. 2008 Jul 24;51(14):4280-8
references.pmid: 18578469
references.citation: J Chem Inf Model. 2007 Jan-Feb;47(1):122-33
references.pmid: 17238257
references.citation: Biochem Biophys Res Commun. 2010 Mar 5;393(2):207-10
references.pmid: 20122900
references.citation: J Comput Chem. 2005 Jul 15;26(9):915-31
references.pmid: 15841474
references.citation: Science. 2003 Oct 24;302(5645):636-9
references.pmid: 14576432
references.citation: Biophys Chem. 1999 Apr 5;78(1-2):195-205
references.pmid: 10343388
references.citation: Nat Genet. 1996 Jul;13(3):266-8
references.pmid: 8673121
references.citation: J Phys Chem A. 2008 Nov 27;112(47):12157-63
references.pmid: 18986122
references.citation: J Natl Cancer Inst. 2004 Nov 17;96(22):1659-68
references.pmid: 15547178
references.citation: J Comput Chem. 2003 Dec;24(16):1999-2012
references.pmid: 14531054
references.citation: Nat Struct Mol Biol. 2004 Jun;11(6):512-8
references.pmid: 15133502
references.citation: J Phys Chem B. 2009 Aug 13;113(32):11085-94
references.pmid: 19618955
references.citation: J Mol Model. 2009 Jul;15(7):765-805
references.pmid: 19066990
references.citation: Mol Cell Biol. 2004 Nov;24(21):9478-86
references.pmid: 15485915
references.citation: Annu Rev Biophys Biomol Struct. 2007;36:21-42
references.pmid: 17201676