title: Effects of knots on protein folding properties.
abstract: This work explores the impact of knots, knot depth and motif of the threading terminus in protein folding properties (kinetics, thermodynamics and mechanism) via extensive Monte Carlo simulations of lattice models. A knotted backbone has no effect on protein thermodynamic stability but it may affect key aspects of folding kinetics. In this regard, we found clear evidence for a functional advantage of knots: knots enhance kinetic stability because a knotted protein unfolds at a distinctively slower rate than its unknotted counterpart. However, an increase in knot deepness does not necessarily lead to more effective changes in folding properties. In this regard, a terminus with a non-trivial conformation (e.g. hairpin) can have a more dramatic effect in enhancing kinetic stability than knot depth. Nevertheless, our results suggest that the probability of the denatured ensemble to keep knotted is higher for proteins with deeper knots, indicating that knot depth plays a role in determining the topology of the denatured state. Refolding simulations starting from denatured knotted conformations show that not every knot is able to nucleate folding and further indicate that the formation of the knotting loop is a key event in the folding of knotted trefoils. They also show that there are specific native contacts within the knotted core that are crucial to keep a native knotting loop in denatured conformations which otherwise have no detectable structure. The study of the knotting mechanism reveals that the threading of the knotting loop generally occurs towards late folding in conformations that exhibit a significant degree of structural consolidation.
authors.affiliation: Centro de Física da Matéria Condensada, Universidade de Lisboa, Lisboa, Portugal ; Departamento de Física, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Soler
authors.forename: Patrícia F N
authors.initials: PF
authors.lastname: Faísca
mesh_terms: D008958:Models, Molecular; D009010:Monte Carlo Method; D011487:Protein Conformation; D011489:Protein Denaturation; D017510:Protein Folding; D055550:Protein Stability; D011506:Proteins / Q000737:chemistry*; D013696:Temperature
chemical_list: D011506:Proteins
references.citation: Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3119-24
references.pmid: 19211785
references.citation: J Mol Biol. 2007 Feb 16;366(2):650-65
references.pmid: 17169371
references.citation: Phys Rev Lett. 1996 Dec 30;77(27):5433-5436
references.pmid: 10062802
references.citation: Mol Cell. 2008 Jun 6;30(5):642-8
references.pmid: 18538662
references.citation: Curr Opin Chem Biol. 2007 Dec;11(6):595-603
references.pmid: 17967433
references.citation: Phys Rev Lett. 2010 Nov 19;105(21):218101
references.pmid: 21231356
references.citation: Proc Natl Acad Sci U S A. 2008 Sep 30;105(39):14844-8
references.pmid: 18806223
references.citation: Protein Sci. 2010 Nov;19(11):2196-209
references.pmid: 20836137
references.citation: Nat Struct Biol. 2000 Apr;7(4):336-42
references.pmid: 10742180
references.citation: J Mol Biol. 2006 Jun 23;359(5):1420-36
references.pmid: 16787779
references.citation: Biophys Chem. 2010 May;148(1-3):1-15
references.pmid: 20199841
references.citation: FEBS J. 2009 May;276(9):2625-35
references.pmid: 19476499
references.citation: Proc Natl Acad Sci U S A. 2010 Nov 30;107(48):20732-7
references.pmid: 21068371
references.citation: Int J Pept Protein Res. 1975;7(6):445-59
references.pmid: 1201909
references.citation: Proc Natl Acad Sci U S A. 2012 Jun 26;109(26):E1715-23
references.pmid: 22685208
references.citation: Protein Eng Des Sel. 2011 Aug;24(8):627-30
references.pmid: 21669955
references.citation: PLoS Comput Biol. 2006 Sep 15;2(9):e122
references.pmid: 16978047
references.citation: FEBS J. 2009 Jan;276(2):365-75
references.pmid: 19077162
references.citation: PLoS One. 2012;7(4):e35599
references.pmid: 22558173
references.citation: FEBS Lett. 2002 May 22;519(1-3):35-40
references.pmid: 12023014
references.citation: Nat Struct Biol. 1997 Jan;4(1):10-9
references.pmid: 8989315
references.citation: PLoS Comput Biol. 2010 Apr 01;6(4):e1000731
references.pmid: 20369018
references.citation: J Phys Condens Matter. 2011 Jan 26;23(3):033101
references.pmid: 21406854
references.citation: J Mol Biol. 2007 Oct 12;373(1):153-66
references.pmid: 17764691
references.citation: Biophys J. 2012 Feb 8;102(3):569-78
references.pmid: 22325280
references.citation: Proc Natl Acad Sci U S A. 2010 May 4;107(18):8189-94
references.pmid: 20393125
references.citation: Phys Rev E Stat Nonlin Soft Matter Phys. 2013 Jan;87(1):012706
references.pmid: 23410358
references.citation: J Mol Biol. 2007 May 4;368(3):884-93
references.pmid: 17368671
references.citation: Proc Natl Acad Sci U S A. 2012 Oct 30;109(44):17783-8
references.pmid: 22891304
references.citation: Nucleic Acids Res. 2012 Jul;40(Web Server issue):W228-31
references.pmid: 22693223
references.citation: Nat Chem Biol. 2011 Dec 18;8(2):147-53
references.pmid: 22179065
references.citation: Biochemistry. 1994 Aug 23;33(33):10026-36
references.pmid: 8060971
references.citation: Biophys Chem. 2005 Apr 1;115(2-3):169-75
references.pmid: 15752600
references.citation: Phys Biol. 2013 Feb;10(1):016002
references.pmid: 23283414
references.citation: Phys Rev E Stat Phys Plasmas Fluids Relat Interdiscip Topics. 1995 Jul;52(1):1176-1180
references.pmid: 9963522
references.citation: J Mol Graph Model. 2004 May;22(5):377-95
references.pmid: 15099834
references.citation: PLoS One. 2012;7(12):e52343
references.pmid: 23284997
references.citation: Nature. 2000 Aug 24;406(6798):916-9
references.pmid: 10972297
references.citation: Proc Natl Acad Sci U S A. 2010 Aug 31;107(35):15403-8
references.pmid: 20702769
references.citation: Proc Natl Acad Sci U S A. 2008 Dec 2;105(48):18740-5
references.pmid: 19015517
references.citation: Phys Biol. 2010 Feb 03;7(1):16009
references.pmid: 20130340
references.citation: J Mol Biol. 2009 Oct 9;392(5):1303-14
references.pmid: 19576901
references.citation: J Phys Condens Matter. 2009 Sep 16;21(37):373102
references.pmid: 21832332
references.citation: Proc Natl Acad Sci U S A. 2008 Dec 16;105(50):19714-9
references.pmid: 19064918
references.citation: PLoS Comput Biol. 2012;8(6):e1002504
references.pmid: 22719235