title: The dynamics of interconverting D- and E-forms of the HIV-1 integrase N-terminal domain.
abstract: The N-terminal domain (NTD) of HIV-1 integrase adopts two inter-converting forms (D- and E-) due to their specific coordination of a Zn(2+) ion by an HHCC motif. Mutational studies on NTD have suggested the importance of conformational transition in regulating the functions of tetramers and dimers of HIV-1 integrase. This study explores the stability and dynamics of native NTD forms and the conformational transition between D- and E-forms using molecular dynamics simulations elucidating their role in regulation of viral and host DNA integration. Simulation of native forms of NTD revealed stable dynamics. Transition studies between D- and E-forms using conventional molecular dynamics simulations for 50 ns partially revealed conformational change towards the target during D- to -E simulation (the extension of α1-helix), which failed in the E- to -D simulation. This could be attributed to the existence of the D-form (-1,945.907 kCal/mol) in higher energy than the E-form (-2,002.383 kCal/mol). The conformational transition pathway between these two states was explored using targeted molecular dynamics simulations. Analysis of the targeted molecular dynamics trajectories revealed conformations closer to the experimentally-reported intermediate form of an NTD during the transition phase. The role of Met22 in stabilizing the E-form was studied by simulating the E-form with Met22Ala mutation, revealing a highly dynamic α1-helix as compared to the native form. The present study reveals the significant role of the Zn(2+) ion-coordinated HHCC motif and its interaction with Met22 as the basis for understanding the biological implications of D- and E-forms of the NTD in regulating integration reaction.
authors.affiliation: Centre for Bioinformatics, School of Life Sciences, Pondicherry University, Puducherry, 605014, India.
authors.forename: Balasubramanian
authors.initials: B
authors.lastname: Sangeetha
authors.forename: Rajagopalan
authors.initials: R
authors.lastname: Muthukumaran
authors.forename: Ramaswamy
authors.initials: R
authors.lastname: Amutha
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D004795:Enzyme Stability; D019427:HIV Integrase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015032:Zinc / Q000737:chemistry / Q000494:pharmacology
chemical_list: D019427:HIV Integrase; D015032:Zinc; C514801:p31 integrase protein, Human immunodeficiency virus 1
references.citation: J Chem Theory Comput. 2010 Sep 14;6(9):2935-2947
references.pmid: 20856692
references.citation: Biochemistry. 2007 Jun 26;46(25):7383-95
references.pmid: 17547373
references.citation: Nature. 2010 Mar 11;464(7286):232-6
references.pmid: 20118915
references.citation: Proc Natl Acad Sci U S A. 2000 Jul 18;97(15):8233-8
references.pmid: 10890912
references.citation: Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):13659-64
references.pmid: 8942990
references.citation: PLoS One. 2009 Nov 13;4(11):e7825
references.pmid: 19915660
references.citation: J Comput Aided Mol Des. 2004 Dec;18(12):739-60
references.pmid: 16075307
references.citation: EMBO J. 2009 Apr 8;28(7):980-91
references.pmid: 19229293
references.citation: FEBS J. 2009 Jun;276(11):2926-46
references.pmid: 19490099
references.citation: J Mol Graph. 1994 Jun;12(2):84-9
references.pmid: 7918256
references.citation: J Comput Chem. 2005 Dec;26(16):1668-88
references.pmid: 16200636
references.citation: J Biol Chem. 2003 Aug 29;278(35):33528-39
references.pmid: 12796494
references.citation: J Virol. 2006 Jun;80(12):5670-7
references.pmid: 16731905
references.citation: J Virol. 1994 Sep;68(9):5911-7
references.pmid: 8057470
references.citation: Proc Natl Acad Sci U S A. 2010 Sep 7;107(36):15910-5
references.pmid: 20733078
references.citation: Curr Comput Aided Drug Des. 2012 Mar;8(1):70-82
references.pmid: 21999609
references.citation: EMBO J. 1993 Aug;12(8):3269-75
references.pmid: 8344264
references.citation: J Mol Graph Model. 2001;19(1):13-25
references.pmid: 11381523
references.citation: J Virol. 2005 Oct;79(19):12584-91
references.pmid: 16160186
references.citation: Phys Rev B Condens Matter. 1988 Jan 15;37(2):785-789
references.pmid: 9944570
references.citation: J Biol Chem. 2008 Feb 29;283(9):5632-41
references.pmid: 18093980
references.citation: J Comput Aided Mol Des. 2005 May;19(5):301-17
references.pmid: 16184433
references.citation: EMBO J. 1993 Aug;12(8):3261-7
references.pmid: 8344263
references.citation: Biochemistry. 1998 May 12;37(19):6667-78
references.pmid: 9578550
references.citation: PLoS One. 2012;7(5):e37530
references.pmid: 22624045
references.citation: J Chem Phys. 2004 Jun 22;120(24):11919-29
references.pmid: 15268227
references.citation: EMBO J. 2001 Dec 17;20(24):7333-43
references.pmid: 11743009
references.citation: Biopolymers. 1992 May;32(5):523-35
references.pmid: 1515543
references.citation: J Biol Chem. 2003 Jan 3;278(1):372-81
references.pmid: 12407101
references.citation: J Biol Chem. 2013 Mar 8;288(10):7373-86
references.pmid: 23322775
references.citation: Retrovirology. 2008 Dec 17;5:114
references.pmid: 19091057
references.citation: Science. 1994 Dec 23;266(5193):2002-6
references.pmid: 7801128
references.citation: Biochemistry. 1995 Aug 8;34(31):9826-33
references.pmid: 7632683
references.citation: J Biochem. 2006 Apr;139(4):753-9
references.pmid: 16672276
references.citation: J Virol. 1992 Nov;66(11):6361-9
references.pmid: 1404595
references.citation: Protein Sci. 1998 Dec;7(12):2669-74
references.pmid: 9865962
references.citation: Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):9823-7
references.pmid: 7937898
references.citation: Proteins. 1992 Apr;12(4):345-64
references.pmid: 1579569
references.citation: J Phys Chem B. 2012 Jul 26;116(29):8584-603
references.pmid: 22409258
references.citation: Cell. 1997 Feb 21;88(4):483-92
references.pmid: 9038339
references.citation: J Mol Model. 2008 Sep;14(9):857-70
references.pmid: 18594881
references.citation: SAR QSAR Environ Res. 2013;24(9):753-71
references.pmid: 23710969
references.citation: J Chem Theory Comput. 2012 Sep 11;8(9):3314-21
references.pmid: 26605738
references.citation: PLoS Pathog. 2009 Jul;5(7):e1000515
references.pmid: 19609359
references.citation: Biophys J. 1999 Jun;76(6):2999-3011
references.pmid: 10354426
references.citation: Curr HIV Res. 2007 Jul;5(4):365-88
references.pmid: 17627500
references.citation: PLoS One. 2013 Apr 11;8(4):e60734
references.pmid: 23593299
references.citation: Nat Struct Biol. 1997 Jul;4(7):567-77
references.pmid: 9228950
references.citation: Proteins. 2006 Nov 15;65(3):712-25
references.pmid: 16981200
references.citation: Proteins. 1999 May 15;35(3):332-7
references.pmid: 10328268
references.citation: Proc Natl Acad Sci U S A. 1999 Nov 9;96(23):13040-3
references.pmid: 10557269
references.citation: Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3428-32
references.pmid: 8386373
references.citation: Front Microbiol. 2011 Oct 13;2:210
references.pmid: 22016749
references.citation: Annu Rev Biophys. 2008;37:97-116
references.pmid: 18573074
references.citation: J Am Chem Soc. 2004 Mar 3;126(8):2602-12
references.pmid: 14982470
references.citation: Biopolymers. 2003 Jan;68(1):110-20
references.pmid: 12579583
references.citation: J Biomol Struct Dyn. 2012;29(6):659-70
references.pmid: 22545997
references.citation: Proc Natl Acad Sci U S A. 2006 Jan 24;103(4):915-20
references.pmid: 16418268
references.citation: J Virol. 2000 May;74(10):4795-806
references.pmid: 10775618
references.citation: Biochim Biophys Acta. 2009 Sep;1788(9):1804-12
references.pmid: 19540828
references.citation: J Chem Theory Comput. 2011 Feb 8;7(2):525-37
references.pmid: 26596171
references.citation: Proteins. 2001 Nov 15;45(3):176-82
references.pmid: 11599020
references.citation: PLoS Pathog. 2009 Jan;5(1):e1000259
references.pmid: 19132083
references.citation: Proteins. 2002 Oct 1;49(1):1-6
references.pmid: 12211010
references.citation: Acta Crystallogr D Biol Crystallogr. 2003 Feb;59(Pt 2):274-89
references.pmid: 12554938