title: Conformations of intrinsically disordered proteins are influenced by linear sequence distributions of oppositely charged residues.
abstract: The functions of intrinsically disordered proteins (IDPs) are governed by relationships between information encoded in their amino acid sequences and the ensembles of conformations that they sample as autonomous units. Most IDPs are polyampholytes, with sequences that include both positively and negatively charged residues. Accordingly, we focus here on the sequence-ensemble relationships of polyampholytic IDPs. The fraction of charged residues discriminates between weak and strong polyampholytes. Using atomistic simulations, we show that weak polyampholytes form globules, whereas the conformational preferences of strong polyampholytes are determined by a combination of fraction of charged residues values and the linear sequence distributions of oppositely charged residues. We quantify the latter using a patterning parameter κ that lies between zero and one. The value of κ is low for well-mixed sequences, and in these sequences, intrachain electrostatic repulsions and attractions are counterbalanced, leading to the unmasking of preferences for conformations that resemble either self-avoiding random walks or generic Flory random coils. Segregation of oppositely charged residues within linear sequences leads to high κ-values and preferences for hairpin-like conformations caused by long-range electrostatic attractions induced by conformational fluctuations. We propose a scaling theory to explain the sequence-encoded conformational properties of strong polyampholytes. We show that naturally occurring strong polyampholytes have low κ-values, and this feature implies a selection for random coil ensembles. The design of sequences with different κ-values demonstrably alters the conformational preferences of polyampholytic IDPs, and this ability could become a useful tool for enabling direct inquiries into connections between sequence-ensemble relationships and functions of IDPs.
authors.affiliation: Department of Biomedical Engineering and Center for Biological Systems Engineering, Washington University in St. Louis, St. Louis, MO 63130, USA.
authors.forename: Rahul K
authors.initials: RK
authors.lastname: Das
authors.forename: Rohit V
authors.initials: RV
authors.lastname: Pappu
mesh_terms: D000595:Amino Acid Sequence; D002021:Buffers; D008390:Markov Chains; D008956:Models, Chemical; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009010:Monte Carlo Method; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry*; D055672:Static Electricity; D013696:Temperature
chemical_list: D002021:Buffers; D011506:Proteins
references.citation: Proc Natl Acad Sci U S A. 2008 Apr 15;105(15):5762-7
references.pmid: 18391200
references.citation: Phys Rev E Stat Phys Plasmas Fluids Relat Interdiscip Topics. 1994 Nov;50(5):R3322-R3325
references.pmid: 9962501
references.citation: Nat Rev Mol Cell Biol. 2005 Mar;6(3):197-208
references.pmid: 15738986
references.citation: Proc Natl Acad Sci U S A. 2010 Aug 17;107(33):14609-14
references.pmid: 20639465
references.citation: Phys Rev Lett. 2000 Nov 13;85(20):4305-8
references.pmid: 11060624
references.citation: Proc Natl Acad Sci U S A. 2007 Feb 20;104(8):2649-54
references.pmid: 17299036
references.citation: Biophys J. 2012 Apr 4;102(7):1608-16
references.pmid: 22500761
references.citation: Phys Rev E Stat Phys Plasmas Fluids Relat Interdiscip Topics. 2000 Sep;62(3 Pt B):3803-16
references.pmid: 11088898
references.citation: Biochim Biophys Acta. 2010 Jul;1804(7):1500-7
references.pmid: 20307692
references.citation: Proc Natl Acad Sci U S A. 2009 Dec 8;106(49):20740-5
references.pmid: 19933333
references.citation: Methods Enzymol. 2009;469:411-32
references.pmid: 20946801
references.citation: Mol Biosyst. 2012 Jan;8(1):47-57
references.pmid: 21918774
references.citation: Proc Natl Acad Sci U S A. 2010 May 4;107(18):8183-8
references.pmid: 20404210
references.citation: J Comput Chem. 2009 Apr 15;30(5):673-99
references.pmid: 18506808
references.citation: Arch Biochem Biophys. 2008 Jan 1;469(1):132-41
references.pmid: 17931593
references.citation: Methods Mol Biol. 2012;896:107-22
references.pmid: 22821520
references.citation: Biochem J. 2013 Jan 15;449(2):307-18
references.pmid: 23240611
references.citation: Biophys J. 2010 May 19;98(10):2383-90
references.pmid: 20483348
references.citation: Mol Cell. 2012 Jun 29;46(6):871-83
references.pmid: 22749400
references.citation: Eur J Biochem. 2002 Jan;269(1):2-12
references.pmid: 11784292
references.citation: Proc Natl Acad Sci U S A. 2007 Jun 5;104(23):9650-5
references.pmid: 17522259
references.citation: Proc Natl Acad Sci U S A. 2012 Oct 2;109(40):16155-60
references.pmid: 22984159
references.citation: J Mol Biol. 2012 Feb 17;416(2):287-99
references.pmid: 22226835
references.citation: Phys Rev E Stat Phys Plasmas Fluids Relat Interdiscip Topics. 1995 Jul;52(1):835-846
references.pmid: 9963487
references.citation: Mol Cell Endocrinol. 2012 Jan 30;348(2):457-65
references.pmid: 21782886
references.citation: J Muscle Res Cell Motil. 2005;26(6-8):291-301
references.pmid: 16465472
references.citation: Nucleic Acids Res. 2007 Jan;35(Database issue):D786-93
references.pmid: 17145717
references.citation: J Am Chem Soc. 2011 May 18;133(19):7405-15
references.pmid: 21517079
references.citation: PLoS Comput Biol. 2012 Jan;8(1):e1002353
references.pmid: 22253588
references.citation: Prog Biophys Mol Biol. 2001 Jul;76(3):131-73
references.pmid: 11709204
references.citation: Biochem Biophys Res Commun. 2004 Nov 12;324(2):489-96
references.pmid: 15474454
references.citation: J Chem Phys. 2005 Mar 1;122(9):094901
references.pmid: 15836175
references.citation: Proteins. 2000 Nov 15;41(3):415-27
references.pmid: 11025552
references.citation: RNA. 1995 Sep;1(7):663-80
references.pmid: 7585252