title: Quantitatively characterizing the ligand binding mechanisms of choline binding protein using Markov state model analysis.
abstract: Protein-ligand recognition plays key roles in many biological processes. One of the most fascinating questions about protein-ligand recognition is to understand its underlying mechanism, which often results from a combination of induced fit and conformational selection. In this study, we have developed a three-pronged approach of Markov State Models, Molecular Dynamics simulations, and flux analysis to determine the contribution of each model. Using this approach, we have quantified the recognition mechanism of the choline binding protein (ChoX) to be ∼90% conformational selection dominant under experimental conditions. This is achieved by recovering all the necessary parameters for the flux analysis in combination with available experimental data. Our results also suggest that ChoX has several metastable conformational states, of which an apo-closed state is dominant, consistent with previous experimental findings. Our methodology holds great potential to be widely applied to understand recognition mechanisms underlining many fundamental biological processes.
authors.affiliation: Department of Chemistry, Institute for Advance Study and School of Science, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong.
authors.forename: Shuo
authors.initials: S
authors.lastname: Gu
authors.affiliation: Department of Chemistry, Institute for Advance Study and School of Science, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong; Department of Biochemistry, University of Washington, Seattle, Washington, United States of America.
authors.forename: Daniel-Adriano
authors.initials: DA
authors.lastname: Silva
authors.affiliation: Department of Chemistry, Institute for Advance Study and School of Science, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong.
authors.forename: Luming
authors.initials: L
authors.lastname: Meng
authors.affiliation: Department of Chemistry, Institute for Advance Study and School of Science, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong.
authors.forename: Alexander
authors.initials: A
authors.lastname: Yue
authors.affiliation: Department of Chemistry, Institute for Advance Study and School of Science, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong; Division of Biomedical Engineering, Institute for Advance Study and School of Science, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong; Center of Systems Biology and Human Health, Institute for Advance Study and School of Science, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong.
authors.forename: Xuhui
authors.initials: X
authors.lastname: Huang
mesh_terms: D002794:Choline / Q000737:chemistry* / Q000378:metabolism*; D008390:Markov Chains; D026901:Membrane Transport Proteins / Q000737:chemistry* / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D013816:Thermodynamics
chemical_list: D026901:Membrane Transport Proteins; C065637:choline transporter; D002794:Choline
references.citation: Proc Natl Acad Sci U S A. 2014 Jul 15;111(28):10197-202
references.pmid: 24982141
references.citation: Curr Opin Struct Biol. 2009 Apr;19(2):120-7
references.pmid: 19361980
references.citation: Curr Opin Struct Biol. 2008 Apr;18(2):154-62
references.pmid: 18378442
references.citation: Proc Natl Acad Sci U S A. 2009 Nov 10;106(45):19011-6
references.pmid: 19887634
references.citation: Biophys J. 2011 Feb 2;100(3):701-710
references.pmid: 21281585
references.citation: Biochemistry. 2011 Dec 6;50(48):10530-9
references.pmid: 22050600
references.citation: J Chem Phys. 2013 Jul 7;139(1):015102
references.pmid: 23822324
references.citation: Proc Natl Acad Sci U S A. 2009 Nov 17;106(46):19346-51
references.pmid: 19887638
references.citation: Pac Symp Biocomput. 2010;:228-39
references.pmid: 19908375
references.citation: J Phys Chem B. 2011 May 12;115(18):5415-24
references.pmid: 21388153
references.citation: J Am Chem Soc. 2010 Feb 10;132(5):1526-8
references.pmid: 20070076
references.citation: Proc Natl Acad Sci U S A. 2008 Aug 12;105(32):11182-7
references.pmid: 18678900
references.citation: J Chem Theory Comput. 2008 Mar;4(3):435-47
references.pmid: 26620784
references.citation: Protein Sci. 1999 Jun;8(6):1181-90
references.pmid: 10386868
references.citation: Nat Chem Biol. 2009 Nov;5(11):789-96
references.pmid: 19841628
references.citation: Chem Rev. 2004 Aug;104(8):3519-40
references.pmid: 15303825
references.citation: J Am Chem Soc. 2013 Oct 30;135(43):16092-101
references.pmid: 24021023
references.citation: J Phys Chem B. 2012 Oct 25;116(42):12669-76
references.pmid: 22994891
references.citation: Proc Natl Acad Sci U S A. 2009 Aug 25;106(34):14349-54
references.pmid: 19706521
references.citation: J Am Chem Soc. 2012 Feb 1;134(4):2399-406
references.pmid: 22206270
references.citation: Biochemistry. 2010 Mar 9;49(9):1893-902
references.pmid: 20141110
references.citation: J Chem Phys. 2011 May 7;134(17):174105
references.pmid: 21548671
references.citation: J Chem Phys. 2004 Jul 1;121(1):415-25
references.pmid: 15260562
references.citation: Methods. 2009 Oct;49(2):197-201
references.pmid: 19410002
references.citation: Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18496-501
references.pmid: 18000050
references.citation: Protein Sci. 2002 Feb;11(2):184-97
references.pmid: 11790828
references.citation: J Chem Phys. 2007 Apr 21;126(15):155101
references.pmid: 17461665
references.citation: Chem Rev. 2009 Sep;109(9):4108-39
references.pmid: 19522502
references.citation: J Chem Phys. 2008 Aug 14;129(6):064107
references.pmid: 18715051
references.citation: J Chem Phys. 2013 May 7;138(17):174106
references.pmid: 23656113
references.citation: Protein Sci. 2000 Jan;9(1):10-9
references.pmid: 10739242
references.citation: J Phys Chem B. 2008 May 15;112(19):6057-69
references.pmid: 18232681
references.citation: Proc Natl Acad Sci U S A. 2006 Oct 17;103(42):15451-6
references.pmid: 17021015
references.citation: Proc Natl Acad Sci U S A. 2007 Sep 25;104(39):15340-5
references.pmid: 17878309
references.citation: PLoS One. 2012;7(8):e43253
references.pmid: 22916232
references.citation: Protein Eng. 1999 Sep;12(9):713-20
references.pmid: 10506280
references.citation: Curr Opin Struct Biol. 2004 Aug;14(4):495-504
references.pmid: 15313245
references.citation: J Am Chem Soc. 2012 Dec 5;134(48):19869-76
references.pmid: 23148479
references.citation: Curr Opin Struct Biol. 2007 Dec;17(6):633-40
references.pmid: 18024008
references.citation: Biophys J. 2010 Mar 17;98(6):L15-7
references.pmid: 20303846
references.citation: J Biol Chem. 2008 Nov 21;283(47):32848-59
references.pmid: 18779321
references.citation: Proc Natl Acad Sci U S A. 1958 Feb;44(2):98-104
references.pmid: 16590179
references.citation: PLoS Comput Biol. 2010 Dec 02;6(12):e1001015
references.pmid: 21152000
references.citation: J Chem Theory Comput. 2009 Sep 8;5(9):2322
references.pmid: 20174456
references.citation: J Chem Theory Comput. 2011 Apr 12;7(4):1032-44
references.pmid: 26606352
references.citation: J Comput Chem. 2010 Jan 30;31(2):455-61
references.pmid: 19499576
references.citation: PLoS Comput Biol. 2011 May;7(5):e1002054
references.pmid: 21637799
references.citation: Proc Natl Acad Sci U S A. 2009 Nov 24;106(47):19765-9
references.pmid: 19805023
references.citation: Proteins. 2006 Jun 1;63(4):846-67
references.pmid: 16475196
references.citation: Biol Chem. 2009 Nov;390(11):1163-70
references.pmid: 19642870
references.citation: Proc Natl Acad Sci U S A. 2011 Jun 21;108(25):10184-9
references.pmid: 21646537
references.citation: J Chem Phys. 2007 Apr 21;126(15):155102
references.pmid: 17461666
references.citation: Curr Opin Struct Biol. 2011 Feb;21(1):4-11
references.pmid: 21081274
references.citation: Proteins. 2006 Nov 15;65(3):712-25
references.pmid: 16981200
references.citation: Proc Natl Acad Sci U S A. 2014 May 27;111(21):7665-70
references.pmid: 24753580
references.citation: Proteins. 2011 Jul;79(7):2097-108
references.pmid: 21538545
references.citation: J Comput Chem. 2012 Sep 30;33(25):1969-80
references.pmid: 22685077
references.citation: Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):13737-41
references.pmid: 19666553
references.citation: Proc Natl Acad Sci U S A. 1999 Aug 31;96(18):9970-2
references.pmid: 10468538
references.citation: Nature. 2007 Oct 25;449(7165):1078-82
references.pmid: 17960247
references.citation: J Chem Phys. 2013 Sep 28;139(12):121905
references.pmid: 24089717
references.citation: J Bacteriol. 2004 Sep;186(18):5988-96
references.pmid: 15342567
references.citation: Curr Opin Struct Biol. 2014 Apr;25:135-44
references.pmid: 24836551
references.citation: J Chem Phys. 2007 Jan 7;126(1):014101
references.pmid: 17212484
references.citation: J Mol Biol. 1999 Feb 12;286(1):279-90
references.pmid: 9931266
references.citation: J Chem Theory Comput. 2012 Mar 13;8(3):1108-20
references.pmid: 26593370
references.citation: PLoS Comput Biol. 2013 Apr;9(4):e1003020
references.pmid: 23592966
references.citation: J Biol Chem. 2012 Oct 5;287(41):34856-65
references.pmid: 22865854