title: The role of select subtype polymorphisms on HIV-1 protease conformational sampling and dynamics.
abstract: HIV-1 protease is an essential enzyme for viral particle maturation and is a target in the fight against HIV-1 infection worldwide. Several natural polymorphisms are also associated with drug resistance. Here, we utilized both pulsed electron double resonance, also called double electron-electron resonance, and NMR (15)N relaxation measurements to characterize equilibrium conformational sampling and backbone dynamics of an HIV-1 protease construct containing four specific natural polymorphisms commonly found in subtypes A, F, and CRF_01 A/E. Results show enhanced backbone dynamics, particularly in the flap region, and the persistence of a novel conformational ensemble that we hypothesize is an alternative flap orientation of a curled open state or an asymmetric configuration when interacting with inhibitors.
authors.affiliation: From the Department of Chemistry, University of Florida, Gainesville, Florida 32611.
authors.forename: Xi
authors.initials: X
authors.lastname: Huang
authors.affiliation: From the Department of Chemistry, University of Florida, Gainesville, Florida 32611.
authors.forename: Manuel D
authors.initials: MD
authors.lastname: Britto
authors.affiliation: From the Department of Chemistry, University of Florida, Gainesville, Florida 32611.
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Kear-Scott
authors.affiliation: the Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida 32610.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Boone
authors.affiliation: the Advanced Magnetic Resonance Imaging and Spectroscopy Facility, McKnight Brain Institute, University of Florida, Gainesville, Florida 32610.
authors.forename: James R
authors.initials: JR
authors.lastname: Rocca
authors.affiliation: the Department of Chemistry, Stony Brook University, Stony Brook, New York 11794, and.
authors.forename: Carlos
authors.initials: C
authors.lastname: Simmerling
authors.affiliation: the Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida 32610.
authors.forename: Robert
authors.initials: R
authors.lastname: Mckenna
authors.affiliation: the Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Bieri
authors.affiliation: the Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Gooley
authors.affiliation: the Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida 32610.
authors.forename: Ben M
authors.initials: BM
authors.lastname: Dunn
authors.affiliation: From the Department of Chemistry, University of Florida, Gainesville, Florida 32611, fanucci@chem.ufl.edu.
authors.forename: Gail E
authors.initials: GE
authors.lastname: Fanucci
mesh_terms: D000595:Amino Acid Sequence; D020134:Catalytic Domain; D016333:HIV Protease / Q000737:chemistry* / Q000235:genetics; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide
chemical_list: D016333:HIV Protease
keywords: Electron Paramagnetic Resonance (EPR); Electron Spin-Label; Flap; HIV-1 Protease; Natural Occurring Polymorphism; Protein Dynamic; Protein Stability; Protein Structure; Pulsed Electron Double Resonance; Salt Bridge
references.citation: J Biol Chem. 2007 Jun 8;282(23):17190-9
references.pmid: 17412697
references.citation: Biomol NMR Assign. 2013 Oct;7(2):199-202
references.pmid: 22752791
references.citation: J Am Chem Soc. 2008 Jun 11;130(23):7184-5
references.pmid: 18479129
references.citation: Bioorg Med Chem Lett. 2006 Apr 1;16(7):1788-94
references.pmid: 16458505
references.citation: J Virol. 2007 Oct;81(19):10209-19
references.pmid: 17634242
references.citation: Proteins. 2009 May 15;75(3):556-68
references.pmid: 18951411
references.citation: Cell Biochem Biophys. 2006;44(3):395-404
references.pmid: 16679526
references.citation: Biochemistry. 2013 May 14;52(19):3278-88
references.pmid: 23566104
references.citation: J Biomol NMR. 2009 Dec;45(4):361-72
references.pmid: 19842046
references.citation: J Biol Chem. 2008 May 9;283(19):13459-70
references.pmid: 18281688
references.citation: Biochim Biophys Acta. 1997 Apr 25;1339(1):113-25
references.pmid: 9165106
references.citation: J Phys Chem B. 2009 Feb 12;113(6):1673-80
references.pmid: 19146430
references.citation: Biochemistry. 1990 Jul 24;29(29):6927-40
references.pmid: 2204424
references.citation: Curr Protoc Protein Sci. 2013 Nov 05;74:17.17.1-17.17.29
references.pmid: 24510645
references.citation: Antivir Ther. 2011;16(3):429-33
references.pmid: 21555827
references.citation: J Am Chem Soc. 2009 Jan 21;131(2):430-1
references.pmid: 19140783
references.citation: J Biomol Struct Dyn. 2013 Dec;31(12):1370-80
references.pmid: 23140382
references.citation: AIDS Rev. 2003 Jul-Sep;5(3):165-71
references.pmid: 14598565
references.citation: J Am Chem Soc. 2009 Oct 21;131(41):14650-1
references.pmid: 19788299
references.citation: Antimicrob Agents Chemother. 2007 Feb;51(2):732-5
references.pmid: 17101675
references.citation: Proc Natl Acad Sci U S A. 2011 Dec 27;108(52):20982-7
references.pmid: 22158985
references.citation: J Biomol NMR. 2011 Jun;50(2):147-55
references.pmid: 21618018
references.citation: Proteins. 2002 Jul 1;48(1):107-16
references.pmid: 12012342
references.citation: Trends Mol Med. 2012 Mar;18(3):182-92
references.pmid: 22240486
references.citation: Biochemistry. 1990 May 15;29(19):4659-67
references.pmid: 2372549
references.citation: AIDS. 1994;8 Suppl 2:S13-28
references.pmid: 7857556
references.citation: J Virol. 2007 May;81(10):5144-54
references.pmid: 17360759
references.citation: J Biomol NMR. 2008 Feb;40(2):107-19
references.pmid: 18085410
references.citation: J Biomol NMR. 1995 Nov;6(3):277-93
references.pmid: 8520220
references.citation: J Virol. 2010 Oct;84(19):9995-10003
references.pmid: 20660190
references.citation: Eur Biophys J. 2009 Jun;38(5):557-68
references.pmid: 19189101
references.citation: J Mol Biol. 2007 Jun 15;369(4):1029-40
references.pmid: 17467738
references.citation: Viruses. 2009 Dec;1(3):1110-36
references.pmid: 21994585
references.citation: Biochemistry. 2012 Apr 3;51(13):2819-28
references.pmid: 22404139
references.citation: Biochemistry. 2003 Dec 30;42(51):15029-35
references.pmid: 14690411
references.citation: Proteins. 2010 Nov 1;78(14):2873-85
references.pmid: 20715057
references.citation: J Mol Model. 2007 Feb;13(2):297-304
references.pmid: 16794810
references.citation: Protein Sci. 2002 Feb;11(2):221-32
references.pmid: 11790832
references.citation: J Mol Biol. 2011 Jul 22;410(4):756-60
references.pmid: 21762813
references.citation: J Mol Biol. 1998 Oct 23;283(2):475-88
references.pmid: 9769219
references.citation: Proc Natl Acad Sci U S A. 2001 May 22;98(11):6062-7
references.pmid: 11353856
references.citation: Adv Protein Chem Struct Biol. 2012;87:57-86
references.pmid: 22607752
references.citation: J Biomol NMR. 1991 May;1(1):99-104
references.pmid: 1668719
references.citation: J Am Chem Soc. 2009 Jan 28;131(3):884-5
references.pmid: 19117390
references.citation: Structure. 1999 Sep 15;7(9):1047-55
references.pmid: 10508781
references.citation: J Antimicrob Chemother. 2013 Oct;68(10):2205-9
references.pmid: 23687186
references.citation: Antimicrob Agents Chemother. 2002 Apr;46(4):1086-92
references.pmid: 11897594
references.citation: J Phys Chem B. 2012 Dec 13;116(49):14235-44
references.pmid: 23167829
references.citation: J Am Chem Soc. 2009 Nov 11;131(44):15978-9
references.pmid: 19886689
references.citation: Proc Natl Acad Sci U S A. 2006 Jan 24;103(4):915-20
references.pmid: 16418268
references.citation: J Biomol NMR. 2008 Feb;40(2):121-33
references.pmid: 18085411
references.citation: Curr HIV Res. 2003 Apr;1(2):239-48
references.pmid: 15043206
references.citation: Biochimie. 1991 Nov;73(11):1391-6
references.pmid: 1799632
references.citation: Biochemistry. 2008 Jan 15;47(2):731-43
references.pmid: 18092815
references.citation: Biochemistry. 2009 Sep 22;48(37):8765-7
references.pmid: 19691291
references.citation: Phys Chem Chem Phys. 2006 Sep 21;8(35):4095-103
references.pmid: 17028698
references.citation: Biochemistry. 1994 Aug 16;33(32):9405-13
references.pmid: 8068616
references.citation: J Chem Theory Comput. 2012 Oct 9;8(10):3452-3462
references.pmid: 23144597
references.citation: Biochemistry. 2012 Oct 9;51(40):7813-5
references.pmid: 23009326
references.citation: Biochemistry. 2002 Jul 9;41(27):8613-9
references.pmid: 12093278