title: Molecular dynamics of the full-length p53 monomer.
abstract: The p53 protein is frequently mutated in a very large proportion of human tumors, where it seems to acquire gain-of-function activity that facilitates tumor onset and progression. A possible mechanism is the ability of mutant p53 proteins to physically interact with other proteins, including members of the same family, namely p63 and p73, inactivating their function. Assuming that this interaction might occurs at the level of the monomer, to investigate the molecular basis for this interaction, here, we sample the structural flexibility of the wild-type p53 monomeric protein. The results show a strong stability up to 850 ns in the DNA binding domain, with major flexibility in the N-terminal transactivations domains (TAD1 and TAD2) as well as in the C-terminal region (tetramerization domain). Several stable hydrogen bonds have been detected between N-terminal or C-terminal and DNA binding domain, and also between N-terminal and C-terminal. Essential dynamics analysis highlights strongly correlated movements involving TAD1 and the proline-rich region in the N-terminal domain, the tetramerization region in the C-terminal domain; Lys120 in the DNA binding region. The herein presented model is a starting point for further investigation of the whole protein tetramer as well as of its mutants.
authors: CINECA; Rome, Italy.
authors: Giovanni
authors: G
authors: Chillemi
authors: Pavel
authors: P
authors: Davidovich
authors: Marco
authors: M
authors: D'Abramo
authors: Tazhir
authors: T
authors: Mametnabiev
authors: Alexander Vasilievich
authors: AV
authors: Garabadzhiu
authors: Alessandro
authors: A
authors: Desideri
authors: Gerry
authors: G
authors: Melino
mesh_terms: D004247:DNA / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D055672:Static Electricity; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53; D004247:DNA
keywords: DNA damage; cancer; cell death; p53; p63; p73
references: Mol Cell Biol. 1986 Sep;6(9):3232-9
references: 3023970
references: Cell Death Differ. 2012 Jun;19(6):1038-48
references: 22193543
references: Cell Death Dis. 2012 Mar 15;3:e285
references: 22419114
references: Proc Natl Acad Sci U S A. 2012 Aug 21;109(34):13590-5
references: 22869710
references: Proc Natl Acad Sci U S A. 2008 Oct 28;105(43):16426-31
references: 18940924
references: Nature. 2010 Nov 25;468(7323):572-5
references: 21107428
references: Oncotarget. 2012 May;3(5):586-93
references: 22592113
references: Cell Death Differ. 2012 Sep;19(9):1525-35
references: 22421968
references: Cell Death Dis. 2011 May 12;2:e156
references: 21562588
references: Nature. 2013 Jan 24;493(7433):542-6
references: 23242140
references: J Chem Inf Model. 2008 Oct;48(10):1999-2009
references: 18826207
references: EMBO J. 2006 Nov 1;25(21):5191-200
references: 17053786
references: Proc Natl Acad Sci U S A. 1999 Mar 2;96(5):1875-80
references: 10051562
references: Nature. 2013 Jan 31;493(7434):689-93
references: 23334421
references: Proc Natl Acad Sci U S A. 2011 Dec 27;108(52):21093-8
references: 22160687
references: Nature. 2010 Nov 25;468(7323):567-71
references: 21107427
references: Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15412-7
references: 16234232
references: Aging (Albany NY). 2012 Dec;4(12):923-31
references: 23271007
references: Cell Death Dis. 2012 Apr 26;3:e302
references: 22534828
references: Proc Natl Acad Sci U S A. 2012 Nov 13;109(46):18797-802
references: 23115335
references: Nat Rev Mol Cell Biol. 2011 Apr;12(4):259-65
references: 21427767
references: Proc Natl Acad Sci U S A. 2012 Dec 18;109(51):20931-6
references: 23213260
references: J Mol Graph. 1996 Feb;14(1):33-8, 27-8
references: 8744570
references: Oncotarget. 2012 Feb;3(2):183-94
references: 22383394
references: Aging (Albany NY). 2012 Mar;4(3):159-65
references: 22394614
references: Cell Death Differ. 2012 Jan;19(1):180-3
references: 22095277
references: Cell Death Differ. 2011 Sep;18(9):1487-99
references: 21760596
references: Aging (Albany NY). 2012 Jul;4(7):450-5
references: 22869016
references: Science. 1996 Nov 8;274(5289):948-53
references: 8875929
references: Cell Death Dis. 2012 Jul 26;3:e358
references: 22833097
references: PLoS Comput Biol. 2010 Aug 05;6(8):
references: 20700496
references: Cell. 2012 Jan 20;148(1-2):244-58
references: 22265415
references: EMBO J. 2007 Jul 25;26(14):3463-73
references: 17581633
references: Oncotarget. 2012 Feb;3(2):132-43
references: 22361592
references: Oncotarget. 2011 Dec;2(12):1109-26
references: 22190384
references: Proc Natl Acad Sci U S A. 2013 Jan 2;110(1):E89-98
references: 23236145
references: Oncotarget. 2012 Nov;3(11):1272-83
references: 23174755
references: Cell Death Differ. 2012 Sep;19(9):1561-70
references: 22460322
references: Bioinformatics. 2013 Apr 1;29(7):845-54
references: 23407358
references: Nat Commun. 2013;4:1407
references: 23360998
references: Cell Death Differ. 2012 Apr;19(4):703-12
references: 22052190
references: Biochemistry. 2012 Oct 16;51(41):8053-5
references: 23025236
references: Cell Death Dis. 2012 Feb 09;3:e271
references: 22318540
references: Oncotarget. 2012 Jun;3(6):601-7
references: 22802145
references: Cell Death Dis. 2012 Sep 27;3:e392
references: 23013791
references: Mol Cell. 2003 Mar;11(3):577-90
references: 12667443
references: Nat Protoc. 2010 Apr;5(4):725-38
references: 20360767
references: Cell Death Differ. 2012 Nov;19(11):1741-9
references: 22705848
references: Proc Natl Acad Sci U S A. 2011 Dec 27;108(52):21099-104
references: 22160706
references: Cell Cycle. 2012 Dec 15;11(24):4579-88
references: 23187804
references: Proc Natl Acad Sci U S A. 2012 Jun 12;109(24):9551-6
references: 22628563
references: Oncotarget. 2012 Mar;3(3):228-35
references: 22410433
references: Cell Cycle. 2012 Nov 1;11(21):4033-9
references: 22990386
references: Cell Cycle. 2012 Dec 15;11(24):4589-96
references: 23187810
references: Cell Death Dis. 2012 Oct 04;3:e397
references: 23034332
references: PLoS One. 2011;6(11):e27651
references: 22110706
references: Cell Death Dis. 2012 Oct 11;3:e400
references: 23059819
references: J Phys Chem B. 2007 Oct 4;111(39):11538-45
references: 17824689
references: BMC Genomics. 2010 Feb 10;11 Suppl 1:S5
references: 20158876
references: Cell Cycle. 2012 Jan 15;11(2):216-7
references: 22214666
references: Cell Death Dis. 2012 Oct 04;3:e395
references: 23034330
references: Aging (Albany NY). 2012 Aug;4(8):525-34
references: 22983298
references: Proc Natl Acad Sci U S A. 2012 Dec 11;109(50):20467-72
references: 23169665
references: Proc Natl Acad Sci U S A. 2011 Jan 11;108(2):557-62
references: 21178074
references: Proc Natl Acad Sci U S A. 2009 Oct 20;106(42):17609-10
references: 19826090
references: Mol Cell. 2006 Jun 23;22(6):741-753
references: 16793544
references: Proc Natl Acad Sci U S A. 2012 Oct 30;109(44):18060-5
references: 23077249
references: Cell Cycle. 2012 Nov 1;11(21):3926-31
references: 22987149
references: Cell Death Differ. 2012 Jun;19(6):926-36
references: 22117195
references: Aging (Albany NY). 2012 Oct;4(10):660-1
references: 23128359
references: Cell Death Dis. 2013 Jan 31;4:e480
references: 23370280
references: Cell Death Dis. 2011 Mar 31;2:e136
references: 21451571
references: Cell. 2012 Jun 8;149(6):1183-5
references: 22682240
references: Cell Cycle. 2012 Dec 1;11(23):4474-83
references: 23159862
references: Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2109-14
references: 16461916
references: Cell Death Dis. 2011 Apr 21;2:e148
references: 21509038
references: Oncotarget. 2011 Mar;2(3):234-8
references: 21406728
references: Cell Death Differ. 2011 May;18(5):874-86
references: 21127500
references: Cell Death Differ. 2011 Sep;18(9):1393-402
references: 21372847
references: Biochem Biophys Res Commun. 2006 Apr 28;343(1):110-6
references: 16530164
references: Oncotarget. 2011 Dec;2(12):1203-17
references: 22203497
references: Cell Death Differ. 2012 Oct;19(10):1613-22
references: 22522597
references: Structure. 2009 Feb 13;17(2):202-10
references: 19217391
references: PLoS Comput Biol. 2011 Oct;7(10):e1002238
references: 22028641
references: Cell Cycle. 2012 Dec 1;11(23):4287-8
references: 23095671
references: Cell Death Dis. 2012 Jun 21;3:e324
references: 22717579
references: Proc Natl Acad Sci U S A. 2012 Aug 21;109(34):13584-9
references: 22869713
references: Nucleic Acids Res. 2011 Nov 1;39(20):8960-71
references: 21764777
references: Science. 1994 Jul 15;265(5170):346-55
references: 8023157
references: Structure. 2012 Dec 5;20(12):2014-24
references: 23063560
references: Int J Mol Sci. 2011 Feb 23;12(2):1410-30
references: 21541066
references: Cell Death Dis. 2011 Dec 15;2:e243
references: 22170099
references: Cell Death Dis. 2012 Apr 19;3:e300
references: 22513874
references: Cell Death Dis. 2011 May 26;2:e164
references: 21614094
references: Proc Natl Acad Sci U S A. 2001 Aug 28;98(18):10037-41
references: 11517324
references: Cell Death Differ. 2012 Aug;19(8):1381-9
references: 22388350
references: Cell Cycle. 2012 Jul 15;11(14):2583-4
references: 22751434
references: Nature. 2010 Aug 26;466(7310):1076-81
references: 20740008
references: Cell Death Dis. 2012 Jun 07;3:e318
references: 22673192
references: Cell. 2009 Dec 24;139(7):1327-41
references: 20064378
references: Oncotarget. 2011 Dec;2(12):948-57
references: 22248668
references: Hum Mutat. 2007 Jun;28(6):622-9
references: 17311302
references: Cell Death Differ. 2012 Jun;19(6):980-9
references: 22158418
references: Cell Cycle. 2012 Dec 15;11(24):4661-72
references: 23187802
references: Proc Natl Acad Sci U S A. 2009 Oct 20;106(42):17705-10
references: 19815500
references: Aging (Albany NY). 2012 Jan;4(1):28-39
references: 22289634
references: Genes Dev. 2012 Sep 15;26(18):2009-14
references: 22987635
references: Proc Natl Acad Sci U S A. 2009 Dec 8;106(49):20758-63
references: 19933326
references: Proc Natl Acad Sci U S A. 2010 Apr 20;107(16):7461-6
references: 20351271
references: Science. 1996 Nov 8;274(5289):1001-5
references: 8875926
references: Cell Cycle. 2012 Dec 15;11(24):4552-62
references: 23165211
references: Proc Natl Acad Sci U S A. 2012 Apr 17;109(16):6066-71
references: 22474346
references: Proc Natl Acad Sci U S A. 2013 Mar 5;110(10):3931-6
references: 23417300
references: Cell Death Dis. 2011 May 19;2:e160
references: 21593792
references: Cell. 2013 Apr 11;153(2):449-60
references: 23562644
references: Cell Death Dis. 2011 May 26;2:e162
references: 21614092
references: Cell Death Differ. 2011 Mar;18(3):563-4
references: 21151028
references: Genes Dev. 2008 Oct 1;22(19):2677-91
references: 18805989
references: Genes Dev. 2005 Sep 15;19(18):2122-37
references: 16131611
references: Cell Cycle. 2012 Dec 1;11(23):4436-46
references: 23151455
references: Aging (Albany NY). 2012 Oct;4(10):709-14
references: 23123616
references: Nat Struct Biol. 1995 Apr;2(4):321-33
references: 7796267
references: Cell Death Dis. 2012 Dec 13;3:e442
references: 23235459
references: Nature. 2010 Nov 25;468(7323):519-20
references: 21107421
references: Proc Natl Acad Sci U S A. 2012 Jan 24;109(4):1133-8
references: 22228303
references: Cell Death Differ. 2012 Mar;19(3):451-60
references: 21886179
references: Cell Cycle. 2012 Jul 15;11(14):2591-2
references: 22751433
references: Proc Natl Acad Sci U S A. 2012 Sep 18;109(38):15312-7
references: 22949650
references: Cell Cycle. 2012 Dec 15;11(24):4545-51
references: 23165243
references: Cell Death Dis. 2012 Apr 05;3:e294
references: 22476102
references: Cell Death Differ. 2011 Dec;18(12):1815-24
references: 21941372
references: Cell Death Dis. 2012 Mar 15;3:e286
references: 22419115
references: Cell Cycle. 2012 Dec 15;11(24):4563-9
references: 23165210
references: Cell Cycle. 2012 Jan 15;11(2):214-5
references: 22214668
references: Cell Death Differ. 2011 Dec;18(12):1924-33
references: 21637289
references: Proc Natl Acad Sci U S A. 2012 Sep 25;109(39):15752-6
references: 22972749
references: Oncotarget. 2011 Dec;2(12):1094-108
references: 22190353
references: Trends Cell Biol. 2008 May;18(5):244-52
references: 18406616
references: J Mol Recognit. 2011 Nov-Dec;24(6):1043-55
references: 22038811
references: Proc Natl Acad Sci U S A. 2007 Jul 24;104(30):12324-9
references: 17620598
references: Cell. 2009 Apr 3;137(1):87-98
references: 19345189
references: Cell Death Dis. 2011 Jul 28;2:e184
references: 21796156
references: Cell. 2011 May 13;145(4):571-83
references: 21565614
references: Cell Death Differ. 2012 May;19(5):816-26
references: 22075982
references: Science. 1995 Mar 10;267(5203):1498-502
references: 7878469
references: Cell Death Differ. 2011 Sep;18(9):1391-2
references: 21841805
references: Cell Cycle. 2012 Nov 15;11(22):4113-4
references: 23099923
references: Nature. 2011 May 5;473(7345):105-8
references: 21478871
references: Biophys Chem. 2005 Apr 22;114(2-3):261-71
references: 15829361
references: Proc Natl Acad Sci U S A. 2012 Jul 17;109(29):11788-93
references: 22745160
references: Cell Cycle. 2012 Dec 15;11(24):4570-8
references: 23165212
references: Proc Natl Acad Sci U S A. 2013 Mar 5;110(10):3895-900
references: 23431171
references: Cell Death Differ. 2012 Jul;19(7):1139-51
references: 22281704
references: Cell Death Dis. 2012 Aug 30;3:e383
references: 22932725
references: J Phys Chem B. 2010 Oct 21;114(41):13201-13
references: 20873738
references: Aging (Albany NY). 2012 Mar;4(3):202-5
references: 22388545
references: Proc Natl Acad Sci U S A. 2012 Sep 4;109(36):14387-92
references: 22908277
references: Nature. 2012 Feb 22;482(7386):538-41
references: 22358843
references: Cell Cycle. 2012 Oct 1;11(19):3638-48
references: 22935697
references: Oncotarget. 2011 Jan-Feb;2(1-2):89-98
references: 21399233
references: Annu Rev Biochem. 2008;77:557-82
references: 18410249
references: Cell Death Differ. 2012 Feb;19(2):186-93
references: 22158419
references: Cell Death Differ. 2012 Dec;19(12):1992-2002
references: 22790872
references: Proteins. 2010 Jun;78(8):1950-8
references: 20408171
references: Nature. 2011 Feb 17;470(7334):409-13
references: 21331045
references: Cell Death Differ. 2011 May;18(5):887-96
references: 21127502
references: BMC Bioinformatics. 2008;9 Suppl 1:S17
references: 18315848