Polypeptide chain collapse and protein folding.

Polypeptide chain collapse is an integral component of a protein folding reaction. In this review, experimental characterization of the interplay of polypeptide chain collapse, secondary structure formation, consolidation of the hydrophobic core and the development of tertiary interactions, is scrutinized. In particular, the polypeptide chain collapse reaction is examined in the context of the three phenomenological models of protein folding - the hydrophobic collapse model, the framework model and the nucleation condensation model - which describe different ways by which polypeptide chains are able to fold in biologically relevant time-scales.

[1]  Y. Amemiya,et al.  Fast Compaction of α-Lactalbumin During Folding Studied by Stopped-flow X-ray Scattering , 2002 .

[2]  G. Rose,et al.  A backbone-based theory of protein folding , 2006, Proceedings of the National Academy of Sciences.

[3]  Lisa J Lapidus,et al.  How fast is protein hydrophobic collapse? , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[4]  Satoshi Takahashi,et al.  Specific collapse followed by slow hydrogen-bond formation of beta-sheet in the folding of single-chain monellin. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[5]  Jayant B Udgaonkar,et al.  Multiple routes and structural heterogeneity in protein folding. , 2008, Annual review of biophysics.

[6]  Tamiki Komatsuzaki,et al.  Development of a technique for the investigation of folding dynamics of single proteins for extended time periods , 2007, Proceedings of the National Academy of Sciences.

[7]  Elisha Haas,et al.  Early Closure of Loops in the Refolding of Adenylate Kinase: A Possible Key Role for Non Local Interactions in the Initial Folding Steps , 2009 .

[8]  K. Dill,et al.  Origins of structure in globular proteins. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[9]  C. Matthews,et al.  Transient intermediates in the folding of dihydrofolate reductase as detected by far-ultraviolet circular dichroism spectroscopy. , 1991, Biochemistry.

[10]  A. Fersht,et al.  Folding of chymotrypsin inhibitor 2. 1. Evidence for a two-state transition. , 1991, Biochemistry.

[11]  A. Liwo,et al.  Evidence, from simulations, of a single state with residual native structure at the thermal denaturation midpoint of a small globular protein. , 2010, Journal of the American Chemical Society.

[12]  Martin Gruebele,et al.  Solvent‐tuning the collapse and helix formation time scales of λ6‐85* , 2006 .

[13]  S. Marqusee,et al.  Molten globule unfolding monitored by hydrogen exchange in urea. , 1998, Biochemistry.

[14]  Satoshi Takahashi,et al.  Collapse and search dynamics of apomyoglobin folding revealed by submillisecond observations of alpha-helical content and compactness. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[15]  H. Orland,et al.  DYNAMICS OF THE SWELLING OR COLLAPSE OF A HOMOPOLYMER , 1996 .

[16]  R. L. Baldwin,et al.  A sequential model of nucleation-dependent protein folding: kinetic studies of ribonuclease A. , 1972, Journal of molecular biology.

[17]  J. Udgaonkar,et al.  Mechanism of formation of a productive molten globule form of barstar. , 2002, Biochemistry.

[18]  Ronald Wetzel,et al.  Fluorescence correlation spectroscopy shows that monomeric polyglutamine molecules form collapsed structures in aqueous solutions , 2006, Proceedings of the National Academy of Sciences.

[19]  J. Udgaonkar,et al.  Barrierless evolution of structure during the submillisecond refolding reaction of a small protein , 2008, Proceedings of the National Academy of Sciences.

[20]  J. Straub,et al.  Simulation study of the collapse of linear and ring homopolymers , 1995 .

[21]  Lisa J. Lapidus,et al.  Fast kinetics and mechanisms in protein folding. , 2000, Annual review of biophysics and biomolecular structure.

[22]  G. Krishnamoorthy,et al.  Structure is lost incrementally during the unfolding of barstar , 2001, Nature Structural Biology.

[23]  Klimov,et al.  Criterion that determines the foldability of proteins. , 1996, Physical review letters.

[24]  W. Eaton,et al.  Probing the free-energy surface for protein folding with single-molecule fluorescence spectroscopy , 2002, Nature.

[25]  Benjamin Schuler,et al.  Ultrafast dynamics of protein collapse from single-molecule photon statistics , 2007, Proceedings of the National Academy of Sciences.

[26]  D. Wetlaufer.  Nucleation, rapid folding, and globular intrachain regions in proteins. , 1973, Proceedings of the National Academy of Sciences of the United States of America.

[27]  D. W. Bolen,et al.  Hydrogen Bonding Progressively Strengthens upon Transfer of the Protein Urea-Denatured State to Water and Protecting Osmolytes† , 2010, Biochemistry.

[28]  M. Karplus,et al.  Protein-folding dynamics , 1976, Nature.

[29]  Lisa J. Lapidus,et al.  Kinetics of intramolecular contact formation in a denatured protein. , 2003, Journal of molecular biology.

[30]  E I Shakhnovich,et al.  Is burst hydrophobic collapse necessary for protein folding? , 1995, Biochemistry.

[31]  Kambiz M. Hamadani,et al.  Nonequilibrium single molecule protein folding in a coaxial mixer. , 2008, Biophysical journal.

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

[33]  A. Fersht,et al.  The denatured state of Engrailed Homeodomain under denaturing and native conditions. , 2003, Journal of molecular biology.

[34]  S. Takahashi,et al.  Stepwise formation of alpha-helices during cytochrome c folding. , 2000, Nature structural biology.

[35]  T. Sosnick,et al.  Fast and slow intermediate accumulation and the initial barrier mechanism in protein folding. , 2002, Journal of molecular biology.

[36]  P. Gennes.  Kinetics of collapse for a flexible coil , 1985 .

[37]  Athi N. Naganathan,et al.  Insights into protein folding mechanisms from large scale analysis of mutational effects , 2010, Proceedings of the National Academy of Sciences.

[38]  S. Sugai,et al.  Unfolding of the molten globule state of alpha-lactalbumin studied by 1H NMR. , 1993, Biochemistry.

[39]  Christopher M. Dobson,et al.  A residue-specific NMR view of the non-cooperative unfolding of a molten globule , 1997, Nature Structural Biology.

[40]  G. Rose,et al.  Counting peptide‐water hydrogen bonds in unfolded proteins , 2011, Protein science : a publication of the Protein Society.

[41]  Satoshi Takahashi,et al.  Time-resolved small-angle X-ray scattering investigation of the folding dynamics of heme oxygenase: implication of the scaling relationship for the submillisecond intermediates of protein folding. , 2006, Journal of molecular biology.

[42]  P. Privalov,et al.  Thermodynamic investigations of proteins. III. Thermodynamic description of lysozyme. , 1976, Biophysical chemistry.

[43]  Athi N. Naganathan,et al.  Protein folding kinetics: barrier effects in chemical and thermal denaturation experiments. , 2007, Journal of the American Chemical Society.

[44]  Jeremy C. Smith,et al.  Hydrogen-Bond Driven Loop-Closure Kinetics in Unfolded Polypeptide Chains , 2010, PLoS Comput. Biol..

[45]  Jayant B Udgaonkar,et al.  Increasing stability reduces conformational heterogeneity in a protein folding intermediate ensemble. , 2004, Journal of molecular biology.

[46]  H. Roder,et al.  Evidence for barrier-limited protein folding kinetics on the microsecond time scale , 1998, Nature Structural Biology.

[47]  K. Dill,et al.  Protein stability: electrostatics and compact denatured states. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[48]  J. Udgaonkar,et al.  Early events in protein folding , 2009 .

[49]  A. Fersht,et al.  Circular dichroism studies of barnase and its mutants: characterization of the contribution of aromatic side chains. , 1993, Biochemistry.

[50]  Everett A Lipman,et al.  Single-Molecule Measurement of Protein Folding Kinetics , 2003, Science.

[51]  Vladimir N Uversky,et al.  What does it mean to be natively unfolded? , 2002, European journal of biochemistry.

[52]  D. Baker,et al.  An α-Helical Burst in the src SH3 Folding Pathway , 2007 .

[53]  V. Uversky,et al.  Why are “natively unfolded” proteins unstructured under physiologic conditions? , 2000, Proteins.

[54]  E. Henry,et al.  Relaxation rate for an ultrafast folding protein is independent of chemical denaturant concentration. , 2007, Journal of the American Chemical Society.

[55]  G. G. Stokes.  "J." , 1890, The New Yale Book of Quotations.

[56]  G. Nienhaus,et al.  Single-molecule FRET study of denaturant induced unfolding of RNase H. , 2006, Journal of molecular biology.

[57]  Hannes Neuweiler,et al.  Backbone-driven collapse in unfolded protein chains. , 2011, Journal of molecular biology.

[58]  K. Dill,et al.  Polymer principles in protein structure and stability. , 1991, Annual review of biophysics and biophysical chemistry.

[59]  Linlin Qiu,et al.  Fast chain contraction during protein folding: "foldability" and collapse dynamics. , 2003, Physical review letters.

[60]  W. Eaton,et al.  Two-state expansion and collapse of a polypeptide. , 2000, Journal of molecular biology.

[61]  J. Udgaonkar,et al.  Initial hydrophobic collapse in the folding of barstar , 1995, Nature.

[62]  K. Hodgson,et al.  Kinetics of lysozyme refolding: structural characterization of a non-specifically collapsed state using time-resolved X-ray scattering. , 1998, Journal of molecular biology.

[63]  H. Scheraga,et al.  Statistical mechanics of noncovalent bonds in polyamino acids. IX. The two‐state theory of protein denaturation , 1965 .

[64]  N. A. Rodionova,et al.  Study of the “molten globule” intermediate state in protein folding by a hydrophobic fluorescent probe , 1991, Biopolymers.

[65]  G. Rose,et al.  Dry molten globule intermediates and the mechanism of protein unfolding , 2010, Proteins.

[66]  J. Udgaonkar,et al.  Differential salt-induced stabilization of structure in the initial folding intermediate ensemble of barstar. , 2002, Journal of molecular biology.

[67]  M. J. Parker,et al.  The cooperativity of burst phase reactions explored. , 1999, Journal of molecular biology.

[68]  N. Go.  Theoretical studies of protein folding. , 1983, Annual review of biophysics and bioengineering.

[69]  R. Woody.  Aromatic side‐chain contributions to the far ultraviolet circular dichroism of peptides and proteins , 1978 .

[70]  S. Hagen.  Exponential decay kinetics in “downhill” protein folding , 2002, Proteins.

[71]  Peter E Wright,et al.  Modeling transient collapsed states of an unfolded protein to provide insights into early folding events , 2008, Proceedings of the National Academy of Sciences.

[72]  B. Fierz,et al.  Dynamics of unfolded polypeptide chains as model for the earliest steps in protein folding. , 2003, Journal of molecular biology.

[73]  J. Hofrichter,et al.  Submillisecond protein folding kinetics studied by ultrarapid mixing. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[74]  R. Dror,et al.  How Fast-Folding Proteins Fold , 2011, Science.

[75]  M. Gruebele.  Downhill protein folding: evolution meets physics. , 2005, Comptes rendus biologies.

[76]  Vincent A. Voelz,et al.  Slow unfolded-state structuring in Acyl-CoA binding protein folding revealed by simulation and experiment. , 2012, Journal of the American Chemical Society.

[77]  J. Udgaonkar,et al.  Effect of salt on the urea-unfolded form of barstar probed by m value measurements. , 2004, Biochemistry.

[78]  Shuji Akiyama,et al.  Hierarchical folding mechanism of apomyoglobin revealed by ultra-fast H/D exchange coupled with 2D NMR , 2008, Proceedings of the National Academy of Sciences.

[79]  P. S. Kim,et al.  Specific intermediates in the folding reactions of small proteins and the mechanism of protein folding. , 1982, Annual review of biochemistry.

[80]  M. L. Tasayco,et al.  Proline isomerization-independent accumulation of an early intermediate and heterogeneity of the folding pathways of a mixed alpha/beta protein, Escherichia coli thioredoxin. , 1998, Biochemistry.

[81]  J. Udgaonkar,et al.  Dissecting the non-specific and specific components of the initial folding reaction of barstar by multi-site FRET measurements. , 2007, Journal of molecular biology.

[82]  V. Uversky,et al.  The chicken–egg scenario of protein folding revisited , 2002, FEBS letters.

[83]  S. Mukhopadhyay,et al.  Chain collapse of an amyloidogenic intrinsically disordered protein. , 2011, Biophysical journal.

[84]  David A Agard,et al.  How general is the nucleation–condensation mechanism? , 2008, Proteins.

[85]  J. Udgaonkar,et al.  Dynamics of the core tryptophan during the formation of a productive molten globule intermediate of barstar. , 2003, Biochemistry.

[86]  J. Udgaonkar,et al.  Motional dynamics of a buried tryptophan reveals the presence of partially structured forms during denaturation of barstar. , 1996, Biochemistry.

[87]  E. Haas,et al.  Fast collapse but slow formation of secondary structure elements in the refolding transition of E. coli adenylate kinase. , 2005, Journal of molecular biology.

[88]  Alan R Davidson,et al.  Protein folding kinetics beyond the phi value: using multiple amino acid substitutions to investigate the structure of the SH3 domain folding transition state. , 2002, Journal of molecular biology.

[89]  M. Saraste,et al.  FEBS Lett , 2000 .

[90]  K. Dill,et al.  Denatured states of proteins. , 1991, Annual review of biochemistry.

[91]  R. Ulbrich-hofmann,et al.  Coulomb forces control the density of the collapsed unfolded state of barstar. , 2008, Journal of molecular biology.

[92]  K. Plaxco,et al.  Small-angle X-ray scattering and single-molecule FRET spectroscopy produce highly divergent views of the low-denaturant unfolded state. , 2012, Journal of molecular biology.

[93]  J. Udgaonkar,et al.  Evidence for initial non-specific polypeptide chain collapse during the refolding of the SH3 domain of PI3 kinase. , 2010, Journal of molecular biology.

[94]  Kevin J. McHale,et al.  Single-Molecule Fluorescence Experiments Determine Protein Folding Transition Path Times , 2012, Science.

[95]  D. Raleigh,et al.  The unfolded state of NTL9 is compact in the absence of denaturant. , 2006, Biochemistry.

[96]  C. Matthews,et al.  Microsecond subdomain folding in dihydrofolate reductase. , 2011, Journal of molecular biology.

[97]  J. Udgaonkar,et al.  Characterization of intra-molecular distances and site-specific dynamics in chemically unfolded barstar: evidence for denaturant-dependent non-random structure. , 2006, Journal of molecular biology.

[98]  C. Batt,et al.  Structural and kinetic characterization of early folding events in β-lactoglobulin , 2001, Nature Structural Biology.

[99]  Frank Küster,et al.  Single-molecule spectroscopy of the temperature-induced collapse of unfolded proteins , 2009, Proceedings of the National Academy of Sciences.

[100]  J. Udgaonkar,et al.  NMR studies of protein folding , 2003 .

[101]  J. Udgaonkar,et al.  Osmolytes Induce Structure in an Early Intermediate on the Folding Pathway of Barstar* , 2004, Journal of Biological Chemistry.

[102]  R. Woody.  Contributions of tryptophan side chains to the far-ultraviolet circular dichroism of proteins , 2004, European Biophysics Journal.

[103]  T. Kiefhaber,et al.  Origin of unusual phi-values in protein folding: evidence against specific nucleation sites. , 2003, Journal of molecular biology.

[104]  H. Scheraga,et al.  The role of hydrophobic interactions in initiation and propagation of protein folding , 2006, Proceedings of the National Academy of Sciences.

[105]  Lisa J. Lapidus,et al.  Protein hydrophobic collapse and early folding steps observed in a microfluidic mixer. , 2007, Biophysical journal.

[106]  Shimon Weiss,et al.  Ruggedness in the folding landscape of protein L , 2008, HFSP journal.

[107]  M Karplus,et al.  Protein folding dynamics: The diffusion‐collision model and experimental data , 1994, Protein science : a publication of the Protein Society.

[108]  G. Rose,et al.  Structure and energetics of the hydrogen-bonded backbone in protein folding. , 2008, Annual review of biochemistry.

[109]  Robin S. Dothager,et al.  Early collapse is not an obligate step in protein folding. , 2004, Journal of molecular biology.

[110]  A L Fink,et al.  Intermediate conformational states of apocytochrome c. , 1993, Biochemistry.

[111]  F. Schmid,et al.  Rapid collapse precedes the fast two-state folding of the cold shock protein. , 2004, Journal of molecular biology.

[112]  A. Fersht.  Optimization of rates of protein folding: the nucleation-condensation mechanism and its implications. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[113]  Lorna J. Smith,et al.  Long-Range Interactions Within a Nonnative Protein , 2002, Science.

[114]  J. Udgaonkar,et al.  Dependence of the size of the initially collapsed form during the refolding of barstar on denaturant concentration: evidence for a continuous transition. , 2005, Journal of molecular biology.

[115]  J. Udgaonkar,et al.  pH-jump-induced folding and unfolding studies of barstar: evidence for multiple folding and unfolding pathways. , 2001, Biochemistry.

[116]  J. Udgaonkar,et al.  Thermodynamics of denaturation of barstar: evidence for cold denaturation and evaluation of the interaction with guanidine hydrochloride. , 1995, Biochemistry.

[117]  E. Kondrashkina,et al.  Microsecond Hydrophobic Collapse in the Folding of Escherichia coli Dihydrofolate Reductase, an α/β-Type Protein , 2007 .

[118]  Miss A.O. Penney.  (b) , 1974, The New Yale Book of Quotations.

[119]  P E Wright,et al.  Formation of a molten globule intermediate early in the kinetic folding pathway of apomyoglobin. , 1993, Science.

[120]  H. Roder,et al.  Early events in protein folding explored by rapid mixing methods. , 2006, Chemical reviews.

[121]  E. Elson,et al.  The kinetics of conformational fluctuations in an unfolded protein measured by fluorescence methods. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[122]  Satoshi Takahashi,et al.  Specifically collapsed intermediate in the early stage of the folding of ribonuclease A. , 2005, Journal of molecular biology.

[123]  The denatured state of N-PGK is compact and predominantly disordered. , 2009, Journal of molecular biology.

[124]  L Mayne,et al.  Ultrafast signals in protein folding and the polypeptide contracted state. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[125]  D. Thirumalai,et al.  Collapse transition in proteins. , 2009, Physical chemistry chemical physics : PCCP.

[126]  W. Webb,et al.  Dynamics of equilibrium structural fluctuations of apomyoglobin measured by fluorescence correlation spectroscopy , 2007, Proceedings of the National Academy of Sciences.

[127]  J. Udgaonkar,et al.  Continuous dissolution of structure during the unfolding of a small protein , 2009, Proceedings of the National Academy of Sciences.

[128]  J. Udgaonkar,et al.  The slow folding reaction of barstar: the core tryptophan region attains tight packing before substantial secondary and tertiary structure formation and final compaction of the polypeptide chain. , 2000, Journal of molecular biology.

[129]  E I Shakhnovich,et al.  Specific nucleus as the transition state for protein folding: evidence from the lattice model. , 1994, Biochemistry.

[130]  Robert L. Baldwin,et al.  NMR evidence for an early framework intermediate on the folding pathway of ribonuclease A , 1988, Nature.

[131]  A. Fersht,et al.  The folding of an enzyme. I. Theory of protein engineering analysis of stability and pathway of protein folding. , 1992, Journal of molecular biology.

[132]  V. Muñoz,et al.  Experimental Identification of Downhill Protein Folding , 2002, Science.

[133]  K. Kuwajima,et al.  Role of the molten globule state in protein folding. , 2000, Advances in protein chemistry.

[134]  Changbong Hyeon,et al.  Theoretical perspectives on protein folding. , 2010, Annual review of biophysics.

[135]  D. Hamada,et al.  Non-native α-helical intermediate in the refolding of β-lactoglobulin, a predominantly β-sheet protein , 1996, Nature Structural Biology.

[136]  K. Dill,et al.  The ultimate speed limit to protein folding is conformational searching. , 2007, Journal of the American Chemical Society.

[137]  Soon-Ho Park,et al.  Folding dynamics of the B1 domain of protein G explored by ultrarapid mixing , 1999, Nature Structural Biology.

[138]  Kevin W Plaxco,et al.  Residues participating in the protein folding nucleus do not exhibit preferential evolutionary conservation. , 2002, Journal of molecular biology.

[139]  P. S. Kim,et al.  A protein dissection study of a molten globule. , 1994, Biochemistry.

[140]  P. Faísca,et al.  The nucleation mechanism of protein folding: a survey of computer simulation studies , 2009, Journal of physics. Condensed matter : an Institute of Physics journal.

[141]  R. Seckler,et al.  Mapping protein collapse with single-molecule fluorescence and kinetic synchrotron radiation circular dichroism spectroscopy , 2006, Proceedings of the National Academy of Sciences.

[142]  D. Raleigh,et al.  The protein folding transition state: what are Phi-values really telling us? , 2005, Protein and peptide letters.

[143]  Y. Kuznetsov,et al.  Kinetics at the collapse transition of homopolymers and random copolymers , 1995 .

[144]  H. Scheraga,et al.  A Method for Predicting Nucleation Sites for Protein Folding Based on Hydrophobic Contacts , 1978 .

[145]  O. Ptitsyn,et al.  [Stages in the mechanism of self-organization of protein molecules]. , 1973, Doklady Akademii nauk SSSR.

[146]  Sheena E. Radford,et al.  Conformational Properties of the Unfolded State of Im7 in Nondenaturing Conditions , 2012, Journal of molecular biology.

[147]  Lisa J Lapidus,et al.  Extremely slow intramolecular diffusion in unfolded protein L , 2010, Proceedings of the National Academy of Sciences.

[148]  T. Kiefhaber,et al.  The speed limit for protein folding measured by triplet-triplet energy transfer. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[149]  T. Kiefhaber,et al.  Direct measurement of nucleation and growth rates in lysozyme folding. , 1997, Biochemistry.

[150]  T. Kiefhaber,et al.  End-to-end distance distributions and intrachain diffusion constants in unfolded polypeptide chains indicate intramolecular hydrogen bond formation , 2006, Proceedings of the National Academy of Sciences.

[151]  H. Roder,et al.  Early kinetic intermediate in the folding of acyl-CoA binding protein detected by fluorescence labeling and ultrarapid mixing , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[152]  A. Fersht,et al.  Structure of the transition state for the folding/unfolding of the barley chymotrypsin inhibitor 2 and its implications for mechanisms of protein folding. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[153]  H. Scheraga,et al.  Ultrarapid mixing experiments shed new light on the characteristics of the initial conformational ensemble during the folding of ribonuclease A. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[154]  L. Reymond,et al.  Charge interactions can dominate the dimensions of intrinsically disordered proteins , 2010, Proceedings of the National Academy of Sciences.

[155]  Julie D. Forman-Kay,et al.  NOE data demonstrating a compact unfolded state for an SH3 domain under non-denaturing conditions. , 1999 .

[156]  O. Ptitsyn,et al.  Protein folding and protein evolution: common folding nucleus in different subfamilies of c-type cytochromes? , 1998, Journal of molecular biology.

[157]  K. Dill.  Dominant forces in protein folding. , 1990, Biochemistry.

[158]  L. Stryer,et al.  The interaction of a naphthalene dye with apomyoglobin and apohemoglobin. A fluorescent probe of non-polar binding sites. , 1965, Journal of molecular biology.

[159]  Y. Goto,et al.  Refolding of the immunoglobulin light chain. , 1979, Journal of biochemistry.

[160]  Robin S. Dothager,et al.  Random-coil behavior and the dimensions of chemically unfolded proteins. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[161]  Eilon Sherman,et al.  Coil-globule transition in the denatured state of a small protein. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[162]  K. H. Mok,et al.  A pre-existing hydrophobic collapse in the unfolded state of an ultrafast folding protein , 2007, Nature.