Local secondary structure content predicts folding rates for simple, two-state proteins.

Many single-domain proteins exhibit two-state folding kinetics, with folding rates that span more than six orders of magnitude. A quantity of much recent interest for such proteins is their contact order, the average separation in sequence between contacting residue pairs. Numerous studies have reached the surprising conclusion that contact order is well-correlated with the logarithm of the folding rate for these small, well-characterized molecules. Here, we investigate the physico-chemical basis for this finding by asking whether contact order is actually a composite number that measures the fraction of local secondary structure in the protein; viz. turns, helices, and hairpins. To pursue this question, we calculated the secondary structure content for 24 two-state proteins and obtained coefficients that predict their folding rates. The predicted rates correlate strongly with experimentally determined rates, comparable to the correlation with contact order. Further, these predicted folding rates are correlated strongly with contact order. Our results suggest that the folding rate of two-state proteins is a function of their local secondary structure content, consistent with the hierarchic model of protein folding. Accordingly, it should be possible to utilize secondary structure prediction methods to predict folding rates from sequence alone.

[1]  D. Baker,et al.  Contact order, transition state placement and the refolding rates of single domain proteins. , 1998, Journal of molecular biology.

[2]  V. Muñoz,et al.  Folding dynamics and mechanism of β-hairpin formation , 1997, Nature.

[3]  D Baker,et al.  Topology, stability, sequence, and length: defining the determinants of two-state protein folding kinetics. , 2000, Biochemistry.

[4]  Hongyi Zhou,et al.  Folding rate prediction using total contact distance. , 2002, Biophysical journal.

[5]  T. Sosnick,et al.  Molecular collapse: The rate‐limiting step in two‐state cytochrome c folding , 1996, Proteins.

[6]  B. Jonsson,et al.  Remarkably slow folding of a small protein , 1997, FEBS letters.

[7]  G. Rose,et al.  Is protein folding hierarchic? II. Folding intermediates and transition states. , 1999, Trends in biochemical sciences.

[8]  G. N. Ramachandran,et al.  Conformation of polypeptides and proteins. , 1968, Advances in protein chemistry.

[9]  G. Rose,et al.  Hierarchic organization of domains in globular proteins. , 1979, Journal of molecular biology.

[10]  T. Muir,et al.  Rescuing a destabilized protein fold through backbone cyclization. , 2001, Journal of molecular biology.

[11]  W. Goddard,et al.  The topomer-sampling model of protein folding. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[12]  K. Dill,et al.  From Levinthal to pathways to funnels , 1997, Nature Structural Biology.

[13]  A. Fersht,et al.  The structure of the transition state for folding of chymotrypsin inhibitor 2 analysed by protein engineering methods: evidence for a nucleation-condensation mechanism for protein folding. , 1995, Journal of molecular biology.

[14]  R. Srinivasan,et al.  A physical basis for protein secondary structure. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[15]  M. Oliveberg,et al.  High-energy channeling in protein folding. , 1997, Biochemistry.

[16]  J. Onuchic,et al.  Funnels, pathways, and the energy landscape of protein folding: A synthesis , 1994, Proteins.

[17]  G. Rose,et al.  A simple model for polyproline II structure in unfolded states of alanine‐based peptides , 2002, Protein science : a publication of the Protein Society.

[18]  D. Raleigh,et al.  Submillisecond folding of the peripheral subunit-binding domain. , 1999, Journal of molecular biology.

[19]  Aaron R. Dinner,et al.  The roles of stability and contact order in determining protein folding rates , 2001, Nature Structural Biology.

[20]  Martin Karplus,et al.  Application of the diffusion-collision model to the folding of three-helix bundle proteins. , 2002, Journal of molecular biology.

[21]  R. Pappu,et al.  The early folding kinetics of apomyoglobin , 1998, Protein science : a publication of the Protein Society.

[22]  T. N. Bhat,et al.  The Protein Data Bank , 2000, Nucleic Acids Res..

[23]  Kevin W Plaxco,et al.  How the folding rate constant of simple, single-domain proteins depends on the number of native contacts , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[24]  D. Baker,et al.  A surprising simplicity to protein folding , 2000, Nature.

[25]  G. Rose,et al.  Turns in peptides and proteins. , 1985, Advances in protein chemistry.

[26]  George D. Rose,et al.  A protein taxonomy based on secondary structure , 1999, Nature Structural Biology.

[27]  P. R. Bevington,et al.  Data Reduction and Error Analysis for the Physical Sciences , 1969 .

[28]  R. Sauer,et al.  Understanding protein hydrogen bond formation with kinetic H/D amide isotope effects , 2002, Nature Structural Biology.

[29]  T. Oas,et al.  Mechanism of fast protein folding. , 2002, Annual review of biochemistry.

[30]  Terrence G. Oas,et al.  Preorganized secondary structure as an important determinant of fast protein folding , 2001, Nature Structural Biology.

[31]  Kevin W Plaxco,et al.  The topomer search model: A simple, quantitative theory of two‐state protein folding kinetics , 2003, Protein science : a publication of the Protein Society.

[32]  W. Kabsch,et al.  Dictionary of protein secondary structure: Pattern recognition of hydrogen‐bonded and geometrical features , 1983, Biopolymers.

[33]  D. Goldenberg,et al.  φ-Values for BPTI folding intermediates and implications for transition state analysis , 2001, Nature Structural Biology.

[34]  G. Rose,et al.  Is protein folding hierarchic? I. Local structure and peptide folding. , 1999, Trends in biochemical sciences.

[35]  D. Shortle,et al.  Persistence of Native-Like Topology in a Denatured Protein in 8 M Urea , 2001, Science.

[36]  S. Ghaemmaghami,et al.  Folding kinetics of a fluorescent variant of monomeric lambda repressor. , 1998, Biochemistry.

[37]  R. Srinivasan,et al.  Ab initio prediction of protein structure using LINUS , 2002, Proteins.

[38]  A. Fersht,et al.  Protein folding and unfolding in microseconds to nanoseconds by experiment and simulation. , 2000, Proceedings of the National Academy of Sciences of the United States of America.