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Protein Sci. Jan 2000; 9(1): 10–19.
PMCID: PMC2144430

Folding and binding cascades: dynamic landscapes and population shifts.


Whereas previously we have successfully utilized the folding funnels concept to rationalize binding mechanisms (Ma B, Kumar S, Tsai CJ, Nussinov R, 1999, Protein Eng 12:713-720) and to describe binding (Tsai CJ, Kumar S, Ma B, Nussinov R, 1999, Protein Sci 8:1181-1190), here we further extend the concept of folding funnels, illustrating its utility in explaining enzyme pathways, multimolecular associations, and allostery. This extension is based on the recognition that funnels are not stationary; rather, they are dynamic, depending on the physical or binding conditions (Tsai CJ, Ma B, Nussinov R, 1999, Proc Natl Acad Sci USA 96:9970-9972). Different binding states change the surrounding environment of proteins. The changed environment is in turn expressed in shifted energy landscapes, with different shapes and distributions of populations of conformers. Hence, the function of a protein and its properties are not only decided by the static folded three-dimensional structure; they are determined by the distribution of its conformational substates, and in particular, by the redistributions of the populations under different environments. That is, protein function derives from its dynamic energy landscape, caused by changes in its surroundings.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Baker D, Agard DA. Kinetics versus thermodynamics in protein folding. Biochemistry. 1994 Jun 21;33(24):7505–7509. [PubMed]
  • Baldwin RL. Protein folding. Matching speed and stability. Nature. 1994 May 19;369(6477):183–184. [PubMed]
  • Baldwin RL. The nature of protein folding pathways: the classical versus the new view. J Biomol NMR. 1995 Feb;5(2):103–109. [PubMed]
  • Baldwin RL, Rose GD. Is protein folding hierarchic? I. Local structure and peptide folding. Trends Biochem Sci. 1999 Jan;24(1):26–33. [PubMed]
  • Baldwin RL, Rose GD. Is protein folding hierarchic? II. Folding intermediates and transition states. Trends Biochem Sci. 1999 Feb;24(2):77–83. [PubMed]
  • Bennett MJ, Choe S, Eisenberg D. Domain swapping: entangling alliances between proteins. Proc Natl Acad Sci U S A. 1994 Apr 12;91(8):3127–3131. [PMC free article] [PubMed]
  • Bennett MJ, Schlunegger MP, Eisenberg D. 3D domain swapping: a mechanism for oligomer assembly. Protein Sci. 1995 Dec;4(12):2455–2468. [PMC free article] [PubMed]
  • Berger C, Weber-Bornhauser S, Eggenberger J, Hanes J, Plückthun A, Bosshard HR. Antigen recognition by conformational selection. FEBS Lett. 1999 Apr 30;450(1-2):149–153. [PubMed]
  • Bernstein FC, Koetzle TF, Williams GJ, Meyer EF, Jr, Brice MD, Rodgers JR, Kennard O, Shimanouchi T, Tasumi M. The Protein Data Bank: a computer-based archival file for macromolecular structures. J Mol Biol. 1977 May 25;112(3):535–542. [PubMed]
  • Boczko EM, Brooks CL., 3rd First-principles calculation of the folding free energy of a three-helix bundle protein. Science. 1995 Jul 21;269(5222):393–396. [PubMed]
  • D'Alessio G. Oligomer evolution in action? Nat Struct Biol. 1995 Jan;2(1):11–13. [PubMed]
  • Dill KA. Polymer principles and protein folding. Protein Sci. 1999 Jun;8(6):1166–1180. [PMC free article] [PubMed]
  • Dill KA, Chan HS. From Levinthal to pathways to funnels. Nat Struct Biol. 1997 Jan;4(1):10–19. [PubMed]
  • Ellis RJ. Steric chaperones. Trends Biochem Sci. 1998 Feb;23(2):43–45. [PubMed]
  • Foote J, Milstein C. Conformational isomerism and the diversity of antibodies. Proc Natl Acad Sci U S A. 1994 Oct 25;91(22):10370–10374. [PMC free article] [PubMed]
  • Frauenfelder H, Sligar SG, Wolynes PG. The energy landscapes and motions of proteins. Science. 1991 Dec 13;254(5038):1598–1603. [PubMed]
  • Freire E. The propagation of binding interactions to remote sites in proteins: analysis of the binding of the monoclonal antibody D1.3 to lysozyme. Proc Natl Acad Sci U S A. 1999 Aug 31;96(18):10118–10122. [PMC free article] [PubMed]
  • Gerstein M, Krebs W. A database of macromolecular motions. Nucleic Acids Res. 1998 Sep 15;26(18):4280–4290. [PMC free article] [PubMed]
  • Geyer M, Schweins T, Herrmann C, Prisner T, Wittinghofer A, Kalbitzer HR. Conformational transitions in p21ras and in its complexes with the effector protein Raf-RBD and the GTPase activating protein GAP. Biochemistry. 1996 Aug 13;35(32):10308–10320. [PubMed]
  • Gruebele M, Wolynes PG. Satisfying turns in folding transitions. Nat Struct Biol. 1998 Aug;5(8):662–665. [PubMed]
  • Gulukota K, Wolynes PG. Statistical mechanics of kinetic proofreading in protein folding in vivo. Proc Natl Acad Sci U S A. 1994 Sep 27;91(20):9292–9296. [PMC free article] [PubMed]
  • Joyce GF. Evolutionary chemistry: getting there from here. Science. 1997 Jun 13;276(5319):1658–1659. [PubMed]
  • Karplus M. The Levinthal paradox: yesterday and today. Fold Des. 1997;2(4):S69–S75. [PubMed]
  • Chan HS. Kinetics of protein folding. Nature. 1995 Feb 23;373(6516):664–665. [PubMed]
  • Kragelund BB, Osmark P, Neergaard TB, Schiødt J, Kristiansen K, Knudsen J, Poulsen FM. The formation of a native-like structure containing eight conserved hydrophobic residues is rate limiting in two-state protein folding of ACBP. Nat Struct Biol. 1999 Jun;6(6):594–601. [PubMed]
  • Kumar S, Ma B, Tsai CJ, Wolfson H, Nussinov R. Folding funnels and conformational transitions via hinge-bending motions. Cell Biochem Biophys. 1999;31(2):141–164. [PubMed]
  • Lazaridis T, Karplus M. "New view" of protein folding reconciled with the old through multiple unfolding simulations. Science. 1997 Dec 12;278(5345):1928–1931. [PubMed]
  • Lindner AB, Eshhar Z, Tawfik DS. Conformational changes affect binding and catalysis by ester-hydrolysing antibodies. J Mol Biol. 1999 Jan 8;285(1):421–430. [PubMed]
  • Ma B, Kumar S, Tsai CJ, Nussinov R. Folding funnels and binding mechanisms. Protein Eng. 1999 Sep;12(9):713–720. [PubMed]
  • Muller YA, Kelley RF, de Vos AM. Hinge bending within the cytokine receptor superfamily revealed by the 2.4 A crystal structure of the extracellular domain of rabbit tissue factor. Protein Sci. 1998 May;7(5):1106–1115. [PMC free article] [PubMed]
  • Nieslanik BS, Dabrowski MJ, Lyon RP, Atkins WM. Stopped-flow kinetic analysis of the ligand-induced coil-helix transition in glutathione S-transferase A1-1: evidence for a persistent denatured state. Biochemistry. 1999 May 25;38(21):6971–6980. [PubMed]
  • Norel R, Lin SL, Wolfson HJ, Nussinov R. Molecular surface complementarity at protein-protein interfaces: the critical role played by surface normals at well placed, sparse, points in docking. J Mol Biol. 1995 Sep 15;252(2):263–273. [PubMed]
  • Norel R, Petrey D, Wolfson HJ, Nussinov R. Examination of shape complementarity in docking of unbound proteins. Proteins. 1999 Aug 15;36(3):307–317. [PubMed]
  • Onuchic JN, Socci ND, Luthey-Schulten Z, Wolynes PG. Protein folding funnels: the nature of the transition state ensemble. Fold Des. 1996;1(6):441–450. [PubMed]
  • Onuchic JN, Wolynes PG, Luthey-Schulten Z, Socci ND. Toward an outline of the topography of a realistic protein-folding funnel. Proc Natl Acad Sci U S A. 1995 Apr 11;92(8):3626–3630. [PMC free article] [PubMed]
  • Plaxco KW, Simons KT, Baker D. Contact order, transition state placement and the refolding rates of single domain proteins. J Mol Biol. 1998 Apr 10;277(4):985–994. [PubMed]
  • Sabelko J, Ervin J, Gruebele M. Observation of strange kinetics in protein folding. Proc Natl Acad Sci U S A. 1999 May 25;96(11):6031–6036. [PMC free article] [PubMed]
  • Scherzinger E, Sittler A, Schweiger K, Heiser V, Lurz R, Hasenbank R, Bates GP, Lehrach H, Wanker EE. Self-assembly of polyglutamine-containing huntingtin fragments into amyloid-like fibrils: implications for Huntington's disease pathology. Proc Natl Acad Sci U S A. 1999 Apr 13;96(8):4604–4609. [PMC free article] [PubMed]
  • Shinde UP, Liu JJ, Inouye M. Protein memory through altered folding mediated by intramolecular chaperones. Nature. 1997 Oct 2;389(6650):520–522. [PubMed]
  • Sigler PB, Xu Z, Rye HS, Burston SG, Fenton WA, Horwich AL. Structure and function in GroEL-mediated protein folding. Annu Rev Biochem. 1998;67:581–608. [PubMed]
  • Sinclair JF, Shortle D. Analysis of long-range interactions in a model denatured state of staphylococcal nuclease based on correlated changes in backbone dynamics. Protein Sci. 1999 May;8(5):991–1000. [PMC free article] [PubMed]
  • Sprang SR. G protein mechanisms: insights from structural analysis. Annu Rev Biochem. 1997;66:639–678. [PubMed]
  • Stella L, Caccuri AM, Rosato N, Nicotra M, Lo Bello M, De Matteis F, Mazzetti AP, Federici G, Ricci G. Flexibility of helix 2 in the human glutathione transferase P1-1. time-resolved fluorescence spectroscopy. J Biol Chem. 1998 Sep 4;273(36):23267–23273. [PubMed]
  • Todd MJ, Freire E. The effect of inhibitor binding on the structural stability and cooperativity of the HIV-1 protease. Proteins. 1999 Aug 1;36(2):147–156. [PubMed]
  • Tsai CJ, Kumar S, Ma B, Nussinov R. Folding funnels, binding funnels, and protein function. Protein Sci. 1999 Jun;8(6):1181–1190. [PMC free article] [PubMed]
  • Tsai CJ, Ma B, Nussinov R. Folding and binding cascades: shifts in energy landscapes. Proc Natl Acad Sci U S A. 1999 Aug 31;96(18):9970–9972. [PMC free article] [PubMed]
  • Tsai CJ, Maizel JV, Jr, Nussinov R. Distinguishing between sequential and nonsequentially folded proteins: implications for folding and misfolding. Protein Sci. 1999 Aug;8(8):1591–1604. [PMC free article] [PubMed]
  • Tsai CJ, Xu D, Nussinov R. Protein folding via binding and vice versa. Fold Des. 1998;3(4):R71–R80. [PubMed]
  • Vonrhein C, Schlauderer GJ, Schulz GE. Movie of the structural changes during a catalytic cycle of nucleoside monophosphate kinases. Structure. 1995 May 15;3(5):483–490. [PubMed]
  • Wedemayer GJ, Patten PA, Wang LH, Schultz PG, Stevens RC. Structural insights into the evolution of an antibody combining site. Science. 1997 Jun 13;276(5319):1665–1669. [PubMed]
  • Williams DC, Jr, Benjamin DC, Poljak RJ, Rule GS. Global changes in amide hydrogen exchange rates for a protein antigen in complex with three different antibodies. J Mol Biol. 1996 Apr 12;257(4):866–876. [PubMed]
  • Wolynes PG, Onuchic JN, Thirumalai D. Navigating the folding routes. Science. 1995 Mar 17;267(5204):1619–1620. [PubMed]

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