title: Characterization of folding mechanisms of Trp-cage and WW-domain by network analysis of simulations with a hybrid-resolution model.
abstract: In this study, we apply a hybrid-resolution model, namely, PACE, to characterize the free energy surfaces (FESs) of Trp-cage and a WW-domain variant along with the respective folding mechanisms. Unbiased, independent simulations with PACE are found to achieve together multiple folding and unfolding events for both proteins, allowing us to perform network analysis of the FESs to identify folding pathways. PACE reproduces for both proteins expected complexity hidden in the folding FESs, in particular metastable non-native intermediates. Pathway analysis shows that some of these intermediates are, actually, on-pathway folding intermediates and that intermediates kinetically closest to the native states can be either critical on-pathway or off-pathway intermediates, depending on the protein. Apart from general insights into folding, specific folding mechanisms of the proteins are resolved. We find that Trp-cage folds via a dominant pathway in which hydrophobic collapse occurs before the N-terminal helix forms; full incorporation of Trp6 into the hydrophobic core takes place as the last step of folding, which, however, may not be the rate-limiting step. For the WW-domain variant studied, we observe two main folding pathways with opposite orders of formation of the two hairpins involved in the structure; for either pathway, formation of hairpin 1 is more likely to be the rate-limiting step. Altogether, our results suggest that PACE combined with network analysis is a computationally efficient and valuable tool for the study of protein folding.
authors.affiliation: Beckman Institute and ‡Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign , Urbana, Illinois, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Han
authors.forename: Klaus
authors.initials: K
authors.lastname: Schulten
mesh_terms: D016000:Cluster Analysis; D056445:Cytoplasmic Dyneins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D009154:Mutation; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D012997:Solvents / Q000737:chemistry; D013816:Thermodynamics
chemical_list: D010455:Peptides; D012997:Solvents; C508725:Trp-cage peptide; C427758:DYNLL1 protein, human; D056445:Cytoplasmic Dyneins
references.citation: J Am Chem Soc. 2011 Feb 2;133(4):664-7
references.pmid: 21174461
references.citation: Science. 1995 Mar 17;267(5204):1619-20
references.pmid: 7886447
references.citation: Nature. 1976 Apr 1;260(5550):404-6
references.pmid: 1256583
references.citation: Proc Natl Acad Sci U S A. 2008 Feb 19;105(7):2369-74
references.pmid: 18268349
references.citation: PLoS Comput Biol. 2010 Jun 24;6(6):e1000827
references.pmid: 20585614
references.citation: J Chem Phys. 2009 May 28;130(20):205102
references.pmid: 19485483
references.citation: Proteins. 1998 Jul 1;32(1):111-27
references.pmid: 9672047
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. 2010 Jun 15;107(24):10890-5
references.pmid: 20534497
references.citation: PLoS Comput Biol. 2009 Aug;5(8):e1000452
references.pmid: 19662155
references.citation: J Mol Biol. 2001 Aug 10;311(2):373-93
references.pmid: 11478867
references.citation: J Chem Theory Comput. 2010 Nov 9;6(11):3373-89
references.pmid: 26617092
references.citation: Nat Struct Biol. 2002 Jun;9(6):425-30
references.pmid: 11979279
references.citation: Proc Natl Acad Sci U S A. 2006 Jul 11;103(28):10648-53
references.pmid: 16807295
references.citation: Proc Natl Acad Sci U S A. 2004 Oct 12;101(41):14766-70
references.pmid: 15466711
references.citation: Science. 2005 Jul 1;309(5731):75
references.pmid: 15994521
references.citation: Proc Natl Acad Sci U S A. 2012 Oct 30;109(44):17807-13
references.pmid: 22778442
references.citation: Science. 2008 Aug 8;321(5890):798-800
references.pmid: 18687954
references.citation: J Chem Phys. 2011 May 7;134(17):174105
references.pmid: 21548671
references.citation: Proteins. 2008 Mar;70(4):1185-95
references.pmid: 17847092
references.citation: J Chem Phys. 2005 May 8;122(18):184901
references.pmid: 15918759
references.citation: Proteins. 2006 Feb 1;62(2):381-98
references.pmid: 16294329
references.citation: Curr Opin Struct Biol. 2004 Feb;14(1):70-5
references.pmid: 15102452
references.citation: Proc Natl Acad Sci U S A. 2013 Apr 9;110(15):5915-20
references.pmid: 23503848
references.citation: Proc Natl Acad Sci U S A. 2005 Nov 15;102(46):16650-5
references.pmid: 16269542
references.citation: Proc Natl Acad Sci U S A. 1995 Nov 21;92(24):10869-73
references.pmid: 7479900
references.citation: J Chem Phys. 2007 Apr 21;126(15):155101
references.pmid: 17461665
references.citation: Proc Natl Acad Sci U S A. 2006 Oct 24;103(43):15859-64
references.pmid: 17035504
references.citation: Proc Natl Acad Sci U S A. 2009 Jan 6;106(1):73-8
references.pmid: 19114654
references.citation: J Phys Chem B. 2009 Jan 8;113(1):267-74
references.pmid: 19067549
references.citation: Proc Natl Acad Sci U S A. 2005 Dec 27;102(52):18914-9
references.pmid: 16365306
references.citation: J Phys Chem B. 2008 May 15;112(19):6057-69
references.pmid: 18232681
references.citation: J Mol Biol. 2004 Sep 3;342(1):299-306
references.pmid: 15313625
references.citation: J Chem Theory Comput. 2010 Nov 9;6(11):3390-402
references.pmid: 26617093
references.citation: J Comput Chem. 2005 Dec;26(16):1781-802
references.pmid: 16222654
references.citation: J Mol Biol. 2011 Jan 7;405(1):43-8
references.pmid: 20974152
references.citation: Proteins. 1995 Mar;21(3):167-95
references.pmid: 7784423
references.citation: Annu Rev Phys Chem. 1997;48:545-600
references.pmid: 9348663
references.citation: Annu Rev Phys Chem. 2002;53:291-318
references.pmid: 11972010
references.citation: Curr Opin Struct Biol. 2010 Feb;20(1):3-10
references.pmid: 20096562
references.citation: J Chem Phys. 2006 Apr 28;124(16):164902
references.pmid: 16674165
references.citation: J Phys Chem B. 2011 Oct 27;115(42):12315-24
references.pmid: 21902225
references.citation: Proc Natl Acad Sci U S A. 2012 Feb 14;109(7):2330-5
references.pmid: 22308345
references.citation: Nature. 2007 May 3;447(7140):106-9
references.pmid: 17429353
references.citation: Curr Opin Struct Biol. 2006 Feb;16(1):71-8
references.pmid: 16413772
references.citation: Q Rev Biophys. 2002 May;35(2):111-67
references.pmid: 12197302
references.citation: Science. 2010 Oct 15;330(6002):341-6
references.pmid: 20947758
references.citation: Science. 2011 Oct 28;334(6055):517-20
references.pmid: 22034434
references.citation: Structure. 2008 Jul;16(7):1010-8
references.pmid: 18611374
references.citation: Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2605-10
references.pmid: 16478803
references.citation: J Am Chem Soc. 2004 Jun 16;126(23):7238-43
references.pmid: 15186161
references.citation: Science. 1991 Dec 13;254(5038):1598-603
references.pmid: 1749933
references.citation: Biophys J. 2009 Apr 22;96(8):L53-5
references.pmid: 19383445
references.citation: Curr Opin Struct Biol. 2008 Apr;18(2):154-62
references.pmid: 18378442
references.citation: J Chem Theory Comput. 2012 Nov 13;8(11):4413-4424
references.pmid: 23204949
references.citation: Proc Natl Acad Sci U S A. 2009 Nov 10;106(45):19011-6
references.pmid: 19887634
references.citation: Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13280-5
references.pmid: 14581616
references.citation: J Am Chem Soc. 2002 Nov 6;124(44):12952-3
references.pmid: 12405814
references.citation: Biophys J. 2008 Feb 1;94(3):929-37
references.pmid: 17905840
references.citation: J Chem Theory Comput. 2012 Jan 10;8(1):300-13
references.pmid: 26592891
references.citation: J Chem Theory Comput. 2008 Nov 11;4(11):1891-901
references.pmid: 26620333
references.citation: Curr Opin Struct Biol. 2006 Feb;16(1):94-101
references.pmid: 16442278
references.citation: J Phys Chem B. 2010 May 6;114(17):5840-50
references.pmid: 20392111
references.citation: J Chem Phys. 2007 Apr 21;126(15):155102
references.pmid: 17461666
references.citation: Proc Natl Acad Sci U S A. 2002 Apr 16;99(8):5110-4
references.pmid: 11959961
references.citation: Proc Natl Acad Sci U S A. 2007 Feb 6;104(6):1817-22
references.pmid: 17267610
references.citation: J Phys Chem B. 2006 Jun 29;110(25):12689-98
references.pmid: 16800603
references.citation: Q Rev Biophys. 2002 Aug;35(3):205-86
references.pmid: 12599750
references.citation: PLoS Comput Biol. 2009 Jul;5(7):e1000428
references.pmid: 19593364
references.citation: J Mol Biol. 2006 Jul 21;360(4):865-81
references.pmid: 16784750
references.citation: J Phys Chem B. 2008 Jul 24;112(29):8701-14
references.pmid: 18590307
references.citation: J Chem Theory Comput. 2011 Jun 14;7(6):1979-89
references.pmid: 26596457
references.citation: J Phys Chem B. 2007 Jul 12;111(27):7812-24
references.pmid: 17569554
references.citation: Annu Rev Biophys. 2008;37:289-316
references.pmid: 18573083
references.citation: J Chem Theory Comput. 2012 Jul 10;8(7):2223-38
references.pmid: 26588955