title: Perplexing cooperative folding and stability of a low-sequence complexity, polyproline 2 protein lacking a hydrophobic core.
abstract: The burial of hydrophobic side chains in a protein core generally is thought to be the major ingredient for stable, cooperative folding. Here, we show that, for the snow flea antifreeze protein (sfAFP), stability and cooperativity can occur without a hydrophobic core, and without α-helices or β-sheets. sfAFP has low sequence complexity with 46% glycine and an interior filled only with backbone H-bonds between six polyproline 2 (PP2) helices. However, the protein folds in a kinetically two-state manner and is moderately stable at room temperature. We believe that a major part of the stability arises from the unusual match between residue-level PP2 dihedral angle bias in the unfolded state and PP2 helical structure in the native state. Additional stabilizing factors that compensate for the dearth of hydrophobic burial include shorter and stronger H-bonds, and increased entropy in the folded state. These results extend our understanding of the origins of cooperativity and stability in protein folding, including the balance between solvent and polypeptide chain entropies.
authors.affiliation: Department of Chemistry, The University of Chicago, Chicago, IL 60637.
authors.forename: Zachary P
authors.initials: ZP
authors.lastname: Gates
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637.|Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Baxa
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637.
authors.forename: Wookyung
authors.initials: W
authors.lastname: Yu
authors.affiliation: Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637.|Graduate Program in Biophysical Sciences, The University of Chicago, Chicago, IL 60637.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Riback
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Chemistry, The University of Chicago, Chicago, IL 60637.|Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637.|Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637.
authors.forename: Benoît
authors.initials: B
authors.lastname: Roux
authors.affiliation: Department of Chemistry, The University of Chicago, Chicago, IL 60637; trsosnic@uchicago.edu skent@uchicago.edu.|Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637.|Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637.
authors.forename: Stephen B H
authors.initials: SB
authors.lastname: Kent
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637; trsosnic@uchicago.edu skent@uchicago.edu.|Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637.
authors.forename: Tobin R
authors.initials: TR
authors.lastname: Sosnick
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D021301:Antifreeze Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D060829:Arthropod Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D018360:Crystallography, X-Ray; D015870:Gene Expression; D005998:Glycine / Q000737:chemistry* / Q000378:metabolism; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D017510:Protein Folding; D054730:Protein Interaction Domains and Motifs; D055550:Protein Stability; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D005423:Siphonaptera / Q000737:chemistry; D013816:Thermodynamics
chemical_list: D021301:Antifreeze Proteins; D060829:Arthropod Proteins; D010455:Peptides; D011994:Recombinant Proteins; C011083:polyproline; D005998:Glycine
keywords: PP2; cooperativity; hydrogen bonding; kinetics; protein folding