title: A serendipitous survey of prediction algorithms for amyloidogenicity.
abstract: The 17- amino acid N-terminal segment of the Huntingtin protein, htt(NT), grows into stable α-helix rich oligomeric aggregates when incubated under physiological conditions. We examined 15 scrambled sequence versions of an htt(NT) peptide for their stabilities against aggregation in aqueous solution at low micromolar concentration and physiological conditions. Surprisingly, given their derivation from a sequence that readily assembles into highly stable α-helical aggregates that fail to convert into β-structure, we found that three of these scrambled peptides rapidly grow into amyloid-like fibrils, while two others also develop amyloid somewhat more slowly. The other 10 scrambled peptides do not detectibly form any aggregates after 100 h incubation under these conditions. We then analyzed these sequences using four previously described algorithms for predicting the tendencies of peptides to grow into amyloid or other β-aggregates. We found that these algorithms-Zyggregator, Tango, Waltz, and Zipper-varied greatly in the number of sequences predicted to be amyloidogenic and in their abilities to correctly identify the amyloid forming members of this scrambled peptide collection. The results are discussed in the context of a review of the sequence and structural factors currently thought to be important in determining amyloid formation kinetics and thermodynamics.
authors.affiliation: Department of Structural Biology and Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh School of Medicine, Biomedical Sciences Tower 3, 3501 Fifth Avenue, Pittsburgh, PA, 15260.
authors.forename: Bartholomew P
authors.initials: BP
authors.lastname: Roland
authors.forename: Ravindra
authors.initials: R
authors.lastname: Kodali
authors.forename: Rakesh
authors.initials: R
authors.lastname: Mishra
authors.forename: Ronald
authors.initials: R
authors.lastname: Wetzel
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry; D010455:Peptides / Q000737:chemistry; D017433:Protein Structure, Secondary; D011795:Surveys and Questionnaires
chemical_list: D000682:Amyloid; D010455:Peptides
keywords: Tango; Waltz; Zipper; Zyggregator; aggregate; amyloid; huntingtin; kinetics; nucleation; oligomer; polyglutamine; thermodynamics; β-structure
references.citation: J Mol Biol. 2008 Jul 4;380(2):425-36
references.pmid: 18514226
references.citation: EMBO Rep. 2007 Aug;8(8):737-42
references.pmid: 17668004
references.citation: Nat Rev Genet. 2005 Sep;6(9):678-87
references.pmid: 16074985
references.citation: Nature. 2005 Jun 9;435(7043):773-8
references.pmid: 15944695
references.citation: Biochemistry. 2005 Sep 27;44(38):12709-18
references.pmid: 16171385
references.citation: J Mol Biol. 2004 Sep 3;342(1):345-53
references.pmid: 15313629
references.citation: J Mol Biol. 2012 Feb 3;415(5):900-17
references.pmid: 22178478
references.citation: PLoS Biol. 2007 Oct 30;5(11):e290
references.pmid: 17973577
references.citation: J Mol Biol. 2012 Nov 23;424(1-2):1-14
references.pmid: 22999956
references.citation: J Mol Biol. 2012 Feb 3;415(5):881-99
references.pmid: 22178474
references.citation: Proc Natl Acad Sci U S A. 2006 Mar 14;103(11):4074-8
references.pmid: 16537487
references.citation: Proc Natl Acad Sci U S A. 2002 Dec 24;99(26):16742-7
references.pmid: 12481027
references.citation: Methods Enzymol. 1999;309:217-36
references.pmid: 10507027
references.citation: FEBS Lett. 1992 Jul 27;307(1):20-5
references.pmid: 1639189
references.citation: J Mol Biol. 2012 Aug 24;421(4-5):466-90
references.pmid: 22306404
references.citation: J Mol Biol. 2005 Jul 8;350(2):379-92
references.pmid: 15925383
references.citation: Science. 2012 Mar 9;335(6073):1228-31
references.pmid: 22403391
references.citation: Nat Rev Mol Cell Biol. 2010 Nov;11(11):777-88
references.pmid: 20944667
references.citation: Nat Struct Mol Biol. 2009 Apr;16(4):380-9
references.pmid: 19270701
references.citation: J Agric Food Chem. 2007 Jul 11;55(14):5445-51
references.pmid: 17539659
references.citation: J Mol Biol. 2007 Nov 30;374(3):688-704
references.pmid: 17945257
references.citation: Trends Biotechnol. 1994 May;12(5):193-8
references.pmid: 7764903
references.citation: Nat Struct Mol Biol. 2011 Mar;18(3):328-36
references.pmid: 21317897
references.citation: Methods Enzymol. 2006;413:34-74
references.pmid: 17046390
references.citation: Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3487-92
references.pmid: 20133726
references.citation: N Engl J Med. 1999 Jun 24;340(25):1970-80
references.pmid: 10379022
references.citation: Anal Biochem. 2004 May 1;328(1):67-75
references.pmid: 15081909
references.citation: Protein Eng Des Sel. 2009 Aug;22(8):453-9
references.pmid: 19596696
references.citation: Physiol Rev. 2010 Jul;90(3):905-81
references.pmid: 20664076
references.citation: Biotechnol Bioeng. 2011 Jul;108(7):1494-508
references.pmid: 21480193
references.citation: Biochemistry. 2007 Nov 27;46(47):13505-22
references.pmid: 17979302
references.citation: N Engl J Med. 2003 Aug 7;349(6):583-96
references.pmid: 12904524
references.citation: Curr Opin Struct Biol. 1998 Feb;8(1):101-6
references.pmid: 9519302
references.citation: Adv Biochem Eng Biotechnol. 2004;89:93-142
references.pmid: 15217157
references.citation: Science. 2009 Dec 11;326(5959):1533-7
references.pmid: 20007899
references.citation: Nat Methods. 2010 Mar;7(3):237-42
references.pmid: 20154676
references.citation: J Am Chem Soc. 2011 Mar 30;133(12):4558-66
references.pmid: 21381744
references.citation: Neuron. 2009 Dec 24;64(6):828-40
references.pmid: 20064390
references.citation: Proc Natl Acad Sci U S A. 2005 Feb 1;102(5):1430-5
references.pmid: 15671169
references.citation: Methods Enzymol. 1999;309:256-74
references.pmid: 10507029
references.citation: J Mol Biol. 2004 Aug 27;341(5):1317-26
references.pmid: 15302561
references.citation: Nat Biotechnol. 2004 Oct;22(10):1302-6
references.pmid: 15361882
references.citation: Science. 2000 Aug 25;289(5483):1317-21
references.pmid: 10958771
references.citation: Nature. 2003 Aug 14;424(6950):805-8
references.pmid: 12917692
references.citation: J Mol Biol. 2006 Jan 20;355(3):524-35
references.pmid: 16321399
references.citation: Cold Spring Harb Protoc. 2010 Apr;2010(4):pdb.prot5411
references.pmid: 20360365
references.citation: Q Rev Biophys. 2011 Nov;44(4):467-518
references.pmid: 21729349
references.citation: J Mol Biol. 2012 Sep 21;422(3):390-402
references.pmid: 22683352
references.citation: J Mol Biol. 2013 Apr 12;425(7):1183-97
references.pmid: 23353826