Binding Mechanisms of Intrinsically Disordered Proteins: Theory, Simulation, and Experiment.
In recent years, protein science has been revolutionized by the discovery of intrinsically disordered proteins (IDPs). In contrast to the classical paradigm that a given protein sequence corresponds to a defined structure and an associated function, we now know that proteins can be functional in the absence of a stable three-dimensional structure. In many cases, disordered proteins or protein regions become structured, at least locally, upon interacting with their physiological partners. Many, sometimes conflicting, hypotheses have been put forward regarding the interaction mechanisms of IDPs and the potential advantages of disorder for protein-protein interactions. Whether disorder may increase, as proposed, e.g., in the "fly-casting" hypothesis, or decrease binding rates, increase or decrease binding specificity, or what role pre-formed structure might play in interactions involving IDPs (conformational selection vs. induced fit), are subjects of intense debate. Experimentally, these questions remain difficult to address. Here, we review experimental studies of binding mechanisms of IDPs using NMR spectroscopy and transient kinetic techniques, as well as the underlying theoretical concepts and numerical methods that can be applied to describe these interactions at the atomic level. The available literature suggests that the kinetic and thermodynamic parameters characterizing interactions involving IDPs can vary widely and that there may be no single common mechanism that can explain the different binding modes observed experimentally. Rather, disordered proteins appear to make combined use of features such as pre-formed structure and flexibility, depending on the individual system and the functional context.
CompuNet, Drug Discovery and Development, Istituto Italiano di Tecnologia Genova, Italy.
Luca
L
Mollica
NMR & Molecular Interactions, Université de Lille, CNRS, UMR 8576 - UGSF - Unité de Glycobiologie Structurale et Fonctionnelle Lille, France.
Luiza M
LM
Bessa
NMR & Molecular Interactions, Université de Lille, CNRS, UMR 8576 - UGSF - Unité de Glycobiologie Structurale et Fonctionnelle Lille, France.
Xavier
X
Hanoulle
Institut de Biologie Structurale, CEA, CNRS, Université Grenoble Alpes Grenoble, France.
Malene Ringkjøbing
MR
Jensen
Institut de Biologie Structurale, CEA, CNRS, Université Grenoble Alpes Grenoble, France.
Martin
M
Blackledge
NMR & Molecular Interactions, Université de Lille, CNRS, UMR 8576 - UGSF - Unité de Glycobiologie Structurale et Fonctionnelle Lille, France.
Robert
R
Schneider
intrinsically disordered proteins; kinetics; molecular dynamics simulations; nuclear magnetic resonance; protein-protein interactions
Proc Natl Acad Sci U S A. 2015 Mar 17;112(11):3409-14
25737554
Trends Biochem Sci. 2005 Sep;30(9):484-9
16054818
J Mol Biol. 2004 May 14;338(5):1015-26
15111064
PLoS Pathog. 2011 Sep;7(9):e1002248
21960769
Proteins. 2010 Jun;78(8):1950-8
20408171
Biochemistry. 2002 Jan 8;41(1):1-7
11771996
Proc Natl Acad Sci U S A. 2013 Sep 10;110(37):14942-7
23980173
Annu Rev Biophys. 2008;37:215-46
18573080
ACS Chem Biol. 2015 Mar 20;10(3):795-802
25511246
Phys Chem Chem Phys. 2014 Apr 14;16(14):6323-31
24317797
Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):12562-6
12271136
Protein Sci. 1994 Apr;3(4):650-68
8003983
PLoS Comput Biol. 2013;9(11):e1003363
24278008
Curr Opin Struct Biol. 1997 Feb;7(1):10-4
9032067
J Phys Chem Lett. 2016 Jul 7;7(13):2483-9
27300592
Curr Opin Struct Biol. 2012 Feb;22(1):21-9
22129832
J Chem Inf Model. 2015 May 26;55(5):1021-9
25919886
J Mol Biol. 2014 Jan 9;426(1):62-70
24120941
Biophys J. 2014 Apr 15;106(8):1771-9
24739176
Mol Biosyst. 2012 Jan;8(1):256-67
21892446
Biophys Chem. 2014 May;189:33-9
24747333
Nature. 2002 Jan 31;415(6871):549-53
11823864
J Mol Biol. 1999 Oct 22;293(2):321-31
10550212
Proc Natl Acad Sci U S A. 2014 Apr 22;111(16):E1557-8
24639541
Phys Rev Lett. 2008 Jan 18;100(2):020603
18232845
Biophys Chem. 2004 Feb 15;107(3):213-20
14967236
Proc Natl Acad Sci U S A. 2008 Nov 18;105(46):17772-7
19008353
Chem Biol Drug Des. 2014 Sep;84(3):253-69
24589355
Sci Rep. 2013;3:2076
23799450
Adv Enzymol Relat Subj Biochem. 1963;25:1-38
14149678
Proc Natl Acad Sci U S A. 1966 Dec;56(6):1661-7
16591399
Proc Natl Acad Sci U S A. 2010 Jul 13;107(28):12535-40
20616042
Proc Natl Acad Sci U S A. 2014 Aug 19;111(33):12055-60
25092343
J Biol Chem. 2008 Sep 26;283(39):26297-301
18544537
Proc Natl Acad Sci U S A. 2014 Oct 28;111(43):15420-5
25313042
Nat Rev Mol Cell Biol. 2015 Jan;16(1):18-29
25531225
Nat Chem Biol. 2014 Dec;10 (12 ):1000-2
25362358
Curr Opin Struct Biol. 2002 Feb;12(1):54-60
11839490
Genome Inform Ser Workshop Genome Inform. 2000;11:161-71
11700597
J Mol Biol. 2010 Apr 30;398(2):200-13
20226197
Biochemistry. 2015 Aug 4;54(30):4741-50
26153298
J Mol Biol. 2012 Oct 19;423(2):182-97
22789567
J Magn Reson. 2008 Jun;192(2):252-7
18378475
Angew Chem Int Ed Engl. 2014 Feb 3;53(6):1548-51
24449148
Trends Biochem Sci. 2009 Dec;34(12):601-11
19846313
Science. 1996 Nov 8;274(5289):948-53
8875929
J Phys Chem B. 2015 Jun 25;119(25):7975-84
26030189
Biochimie. 2007 Mar;89(3):419-21
17174464
Phys Rev E Stat Nonlin Soft Matter Phys. 2014 Oct;90(4):042709
25375525
Nucleic Acids Res. 2007 Jan;35(Database issue):D786-93
17145717
J Am Chem Soc. 2015 Jan 28;137(3):1220-9
25551399
J Mol Graph Model. 2001;19(1):26-59
11381529
Science. 1988 Jun 17;240(4859):1648-52
3381086
Science. 1994 Feb 11;263(5148):777-84
8303294
J Chem Theory Comput. 2014 Nov 11;10(11):5081-94
26584388
Biochemistry. 2002 May 28;41(21):6573-82
12022860
Biophys Chem. 2005 Aug 1;116(3):251-6
15896898
Nucleic Acids Res. 2004 Feb 11;32(3):1037-49
14960716
J Chem Theory Comput. 2015 Nov 10;11(11):5513-24
26574339
J Am Chem Soc. 2012 Feb 29;134(8):3787-91
22339051
J Biol Chem. 2015 Jul 31;290(31):19104-20
26085105
Biochemistry. 2013 Aug 27;52(34):5723-9
23947609
Biochemistry. 2008 May 20;47(20):5481-92
18412369
J Chem Theory Comput. 2015 Apr 14;11(4):1896-906
26574394
Protein Sci. 2002 Oct;11(10):2351-61
12237457
J Chem Theory Comput. 2015 Jul 14;11(7):3420-31
26575776
Anal Chem. 2013 Feb 19;85(4):2449-56
23327569
J Am Chem Soc. 2011 Jul 6;133(26):9976-9
21648484
J Am Chem Soc. 2013 Jan 30;135(4):1415-22
23301700
Protein Sci. 2000 Dec;9(12):2528-34
11206074
Proc Natl Acad Sci U S A. 2011 Jun 14;108(24):9839-44
21613569
Biochem Biophys Res Commun. 2009 May 8;382(3):479-82
19265676
Biochemistry. 2002 Jan 22;41(3):752-9
11790096
Biochim Biophys Acta. 2013 May;1834(5):847-53
23298543
Methods Mol Biol. 2010;627:15-54
20217612
J Phys Chem B. 2013 Oct 24;117(42):13346-56
23875714
Nature. 2007 Jun 21;447(7147):1021-5
17522630
Methods Enzymol. 2001;339:204-38
11462813
Phys Chem Chem Phys. 2012 Aug 14;14(30):10466-76
22744607
Cell. 2015 Oct 22;163(3):734-45
26456112
Proc Natl Acad Sci U S A. 2013 Oct 1;110(40):E3743-52
24043820
Trends Biochem Sci. 2008 Jan;33(1):2-8
18054235
Protein Sci. 2002 Apr;11(4):739-56
11910019
J Am Chem Soc. 2012 May 16;134(19):8148-61
22554188
PLoS Comput Biol. 2011 Apr;7(4):e1002035
21533067
Trends Biochem Sci. 2012 Feb;37(2):43-8
22154231
J Mol Biol. 2009 Nov 13;393(5):1143-59
19747922
J Am Chem Soc. 2016 Jul 20;138(28):8742-51
27348048
Proc Natl Acad Sci U S A. 2008 Apr 15;105(15):5762-7
18391200
Nat Methods. 2011 Mar;8(3):239-41
21297620
Chem Rev. 2014 Jul 9;114(13):6632-60
24725176
J Am Chem Soc. 2008 Jun 25;130(25):8055-61
18507376
Acc Chem Res. 2015 Dec 15;48(12):3026-35
26575522
J Phys Chem Lett. 2014 Jun 5;5(11):1885-91
26273869
Chem Rev. 2006 May;106(5):1700-19
16683750
Nature. 2016 Feb 4;530(7588):45-50
26808899
Mol Cell. 1998 Sep;2(3):353-9
9774973
J Phys Chem B. 2015 Apr 23;119(16):5113-23
25764013
J Am Chem Soc. 2007 Nov 7;129(44):13406-7
17935336
J Am Chem Soc. 2013 Jul 10;135(27):10155-63
23758617
J Mol Biol. 1995 Nov 24;254(2):260-88
7490748
Curr Opin Struct Biol. 2013 Dec;23(6):887-93
23850142
Angew Chem Int Ed Engl. 2010 Sep 10;49(38):6778-80
20715028
J Mol Graph Model. 2004 May;22(5):425-39
15099838
Mol Cell Biol. 1999 Aug;19(8):5601-7
10409749
Science. 2008 Jun 13;320(5882):1471-5
18556554
J Comput Chem. 2006 Oct;27(13):1548-55
16847934
Proc Natl Acad Sci U S A. 2004 May 25;101(21):7976-81
15150406
Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):13737-41
19666553
PLoS Comput Biol. 2012;8(9):e1002682
23028280
J Mol Biol. 2007 Sep 14;372(2):549-61
17681540
Nat Struct Mol Biol. 2004 Apr;11(4):358-64
15024385
Trends Biochem Sci. 2010 Oct;35(10):539-46
20541943
Proc Natl Acad Sci U S A. 1958 Feb;44(2):98-104
16590179
J Am Chem Soc. 2010 Jun 23;132(24):8407-18
20499903
J Biol Chem. 2002 Nov 1;277(44):42241-8
12196545
Curr Opin Struct Biol. 2016 Feb;36:18-24
26720267
Protein Sci. 1997 Jan;6(1):147-55
9007987
J Am Chem Soc. 2014 Apr 9;136(14):5197-200
24654952
Proc Natl Acad Sci U S A. 2015 Aug 4;112(31):9614-9
26195786
J Phys Chem B. 2009 Jul 2;113(26):9004-15
19514729
Biochem Biophys Res Commun. 2012 Nov 16;428(2):205-9
23026051
Protein Eng. 1999 Sep;12(9):713-20
10506280
Biochemistry. 1991 Jan 15;30(2):526-37
1846299
J Am Chem Soc. 2014 Jan 22;136(3):822-5
24364358
Biochemistry. 2012 Jul 31;51(30):5894-902
22775458
J Biol Chem. 2012 Oct 5;287(41):34316-24
22915588
J Mol Biol. 2004 Mar 26;337(3):521-34
15019774
J Mol Biol. 2012 Oct 5;422(5):674-84
22721951
Nat Rev Mol Cell Biol. 2005 Mar;6(3):197-208
15738986
BMC Genomics. 2008;9 Suppl 1:S1
18366598
J Chem Theory Comput. 2015 Jun 9;11(6):2776-82
26575570
Biochemistry. 2006 Oct 3;45(39):11945-57
17002294
Proc Natl Acad Sci U S A. 2000 Aug 1;97(16):8868-73
10908673
J Chem Phys. 2004 May 22;120(20):9665-78
15267980
Nat Chem Biol. 2009 Nov;5(11):789-96
19841628
Biophys J. 2014 Oct 21;107(8):1997-8
25418181
Biochemistry. 2007 Feb 6;46(5):1423-31
17260972
J Med Chem. 2016 May 12;59(9):4035-61
26807648
J Am Chem Soc. 2012 Feb 29;134(8):3792-803
22280219
J Mol Graph Model. 2016 Jul;68:114-27
27423742
Trends Biochem Sci. 2002 Oct;27(10):527-33
12368089