title: NMR relaxation in proteins with fast internal motions and slow conformational exchange: model-free framework and Markov state simulations.
abstract: Calculating NMR relaxation effects for proteins with dynamics on multiple time scales generally requires very long trajectories based on conventional molecular dynamics simulations. In this report, we have built Markov state models from multiple MD trajectories and used the resulting MSM to capture the very fast internal motions of the protein within a free energy basin on a time scale up to hundreds of picoseconds and the more than 3 orders of magnitude slower conformational exchange between macrostates. To interpret the relaxation data, we derive new equations using the model-free framework which includes two slowly exchanging macrostates, each of which also exhibits fast local motions. Using simulations of HIV-1 protease as an example, we show how the populations of slowly exchanging conformational states as well as order parameters for the different states can be determined from the NMR relaxation data.
authors: Department of Chemistry and Chemical Biology and BioMaPS Institute for Quantitative Biology, Rutgers, the State University of New Jersey, 610 Taylor Road, Piscataway, New Jersey 08854, USA.
authors: Junchao
authors: J
authors: Xia
authors: Nan-jie
authors: NJ
authors: Deng
authors: Ronald M
authors: RM
authors: Levy
mesh_terms: D016333:HIV Protease / Q000737:chemistry* / Q000378:metabolism; D015497:HIV-1 / Q000201:enzymology; D006801:Humans; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008390:Markov Chains; D056004:Molecular Dynamics Simulation
chemical_list: D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1
references: PLoS Comput Biol. 2009 Aug;5(8):e1000452
references: 19662155
references: Biophys J. 1983 Feb;41(2):217-21
references: 6838964
references: Nat Struct Biol. 1995 Apr;2(4):334-8
references: 7796268
references: Chem Rev. 2006 May;106(5):1624-71
references: 16683748
references: Drug Discov Today. 2007 Feb;12(3-4):132-8
references: 17275733
references: Biopolymers. 2012 May;97(5):289-302
references: 22058066
references: J Chem Phys. 2009 May 28;130(20):205102
references: 19485483
references: Proteins. 1998 Jul 1;32(1):7-16
references: 9672038
references: Chem Rev. 2006 May;106(5):1672-99
references: 16683749
references: Proc Natl Acad Sci U S A. 2005 May 10;102(19):6801-6
references: 15800044
references: Nat Chem Biol. 2009 Nov;5(11):789-96
references: 19841628
references: Proteins. 2005 Jan 1;58(1):119-25
references: 15521062
references: J Phys Chem B. 2005 Apr 14;109(14):6722-31
references: 16851756
references: Chem Rev. 2004 Aug;104(8):3623-40
references: 15303831
references: Chem Rev. 2006 Aug;106(8):3055-79
references: 16895318
references: J Chem Theory Comput. 2006 May;2(3):840-57
references: 26626691
references: J Am Chem Soc. 2006 Mar 8;128(9):2812-3
references: 16506755
references: J Am Chem Soc. 2012 Feb 1;134(4):2399-406
references: 22206270
references: J Am Chem Soc. 2008 Jun 11;130(23):7184-5
references: 18479129
references: J Chem Phys. 2011 May 7;134(17):174105
references: 21548671
references: J Phys Chem B. 2009 Aug 27;113(34):11702-9
references: 19655770
references: J Chem Phys. 2004 Jul 1;121(1):415-25
references: 15260562
references: J Am Chem Soc. 2011 Jun 22;133(24):9387-94
references: 21561098
references: J Am Chem Soc. 2009 Jan 21;131(2):430-1
references: 19140783
references: Biopolymers. 2012 May;97(5):276-88
references: 22189655
references: J Chem Phys. 2009 Jul 28;131(4):045106
references: 19655927
references: J Comput Chem. 2004 Mar;25(4):479-99
references: 14735568
references: J Am Chem Soc. 2009 Oct 21;131(41):14650-1
references: 19788299
references: J Chem Theory Comput. 2009 Jul 31;5(9):2544-2564
references: 20419084
references: J Am Chem Soc. 2007 Sep 12;129(36):11004-5
references: 17705389
references: J Am Chem Soc. 2011 Nov 16;133(45):18413-9
references: 21988563
references: J Phys Chem B. 2008 May 15;112(19):6057-69
references: 18232681
references: J Phys Chem B. 2008 May 15;112(19):6013-24
references: 18052365
references: Proc Natl Acad Sci U S A. 2007 Sep 25;104(39):15340-5
references: 17878309
references: Protein Sci. 2002 Aug;11(8):1958-70
references: 12142450
references: J Biomol NMR. 2001 Aug;20(4):297-310
references: 11563554
references: J Phys Chem B. 2011 Feb 17;115(6):1512-23
references: 21254767
references: J Phys Chem B. 2010 Mar 4;114(8):3060-9
references: 20143801
references: J Am Chem Soc. 2002 Apr 24;124(16):4522-34
references: 11960483
references: J Mol Biol. 1999 Jan 15;285(2):727-40
references: 9878440
references: Proteins. 2010 Nov 1;78(14):2873-85
references: 20715057
references: J Biomol NMR. 2004 Jul;29(3):243-57
references: 15213423
references: Curr Opin Struct Biol. 2008 Apr;18(2):154-62
references: 18378442
references: Biophys J. 2006 Jun 1;90(11):3880-5
references: 16533835
references: Proc Natl Acad Sci U S A. 2009 Nov 10;106(45):19011-6
references: 19887634
references: Protein Sci. 2002 Feb;11(2):221-32
references: 11790832
references: J Chem Phys. 2005 Nov 22;123(20):204909
references: 16351319
references: J Biomol NMR. 1996 Oct;8(3):273-84
references: 8953218
references: Methods. 2010 Sep;52(1):99-105
references: 20570730
references: Structure. 1999 Sep 15;7(9):1047-55
references: 10508781
references: Proc Natl Acad Sci U S A. 2011 Jun 21;108(25):10184-9
references: 21646537
references: Structure. 2005 Dec;13(12):1887-95
references: 16338417
references: J Chem Theory Comput. 2007 May;3(3):961-75
references: 26627416
references: J Am Chem Soc. 2007 Mar 21;129(11):3315-27
references: 17319663
references: J Am Chem Soc. 2009 Aug 26;131(33):11811-8
references: 19645490
references: J Chem Phys. 2012 Jan 21;136(3):034108
references: 22280745
references: J Am Chem Soc. 2008 May 14;130(19):6145-58
references: 18412346
references: Proc Natl Acad Sci U S A. 2009 Jul 7;106(27):11016-21
references: 19541602
references: J Am Chem Soc. 2006 Oct 18;128(41):13360-1
references: 17031940
references: Biopolymers. 2000-2001;56(4):275-91
references: 11754341
references: J Struct Biol. 2007 Mar;157(3):606-15
references: 17029846
references: J Comput Chem. 2005 Dec;26(16):1752-80
references: 16211539
references: Proc Natl Acad Sci U S A. 2006 Jan 24;103(4):915-20
references: 16418268
references: J Chem Phys. 2008 Jun 28;128(24):244103
references: 18601313
references: Proteins. 2002 Dec 1;49(4):429-31
references: 12402352
references: Biochemistry. 2009 Sep 22;48(37):8765-7
references: 19691291
references: J Phys Chem B. 2005 Apr 14;109(14):6479-84
references: 16851726
references: Proc Natl Acad Sci U S A. 2009 Mar 10;106(10):3776-81
references: 19225111
references: Structure. 2000 Dec 15;8(12):1259-65
references: 11188690
references: J Phys Chem B. 2008 May 15;112(19):6155-8
references: 18311962
references: J Chem Theory Comput. 2012 Oct 9;8(10):3452-3462
references: 23144597
references: Nat Struct Biol. 1995 Apr;2(4):274-80
references: 7796263
references: Protein Sci. 2004 Apr;13(4):1108-23
references: 15044738