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The role of dynamic conformational ensembles in biomolecular recognition

An Erratum to this article was published on 01 December 2009

This article has been updated

Abstract

Molecular recognition is central to all biological processes. For the past 50 years, Koshland's 'induced fit' hypothesis has been the textbook explanation for molecular recognition events. However, recent experimental evidence supports an alternative mechanism. 'Conformational selection' postulates that all protein conformations pre-exist, and the ligand selects the most favored conformation. Following binding the ensemble undergoes a population shift, redistributing the conformational states. Both conformational selection and induced fit appear to play roles. Following binding by a primary conformational selection event, optimization of side chain and backbone interactions is likely to proceed by an induced fit mechanism. Conformational selection has been observed for protein-ligand, protein-protein, protein-DNA, protein-RNA and RNA-ligand interactions. These data support a new molecular recognition paradigm for processes as diverse as signaling, catalysis, gene regulation and protein aggregation in disease, which has the potential to significantly impact our views and strategies in drug design, biomolecular engineering and molecular evolution.

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Figure 1: Thermodynamic cycle for molecular recognition processes involving induced fit or conformational selection.
Figure 2: Conformational selection in protein-ligand interactions observed by NMR R2 relaxation dispersion experiments.
Figure 3: A schematic illustration of molecular recognition processes involving ubiquitin.
Figure 4: DNA recognition by the lac repressor headpiece.

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  • 28 October 2009

    In the version of this article initially published, in Figure 3 the term "free energy" appears with the horizontal axes rather than the vertical axes of the energy diagrams. The error has been corrected in the HTML and PDF versions of the article.

References

  1. Fischer, E. Einfluss der configuration auf die wirkung der enzyme. Ber. Dtsch. Chem. Ges. 27, 2984–2993 (1894).

    Google Scholar 

  2. Koshland, D.E. Application of a theory of enzyme specificity to protein synthesis. Proc. Natl. Acad. Sci. USA 44, 98–104 (1958).

    CAS  PubMed  Google Scholar 

  3. Frauenfelder, H., Sligar, S.G. & Wolynes, P.G. The energy landscapes and motions of proteins. Science 254, 1598–1603 (1991).

    CAS  PubMed  Google Scholar 

  4. Ma, B., Kumar, S., Tsai, C.J. & Nussinov, R. Folding funnels and binding mechanisms. Protein Eng. 12, 713–720 (1999).

    CAS  PubMed  Google Scholar 

  5. Tsai, C.J., Kumar, S., Ma, B. & Nussinov, R. Folding funnels, binding funnels, and protein function. Protein Sci. 8, 1181–1190 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Tsai, C.J., Ma, B. & Nussinov, R. Folding and binding cascades: shifts in energy landscapes. Proc. Natl. Acad. Sci. USA 96, 9970–9972 (1999).

    CAS  PubMed  Google Scholar 

  7. Foote, J. & Milstein, C. Conformational isomerism and the diversity of antibodies. Proc. Natl. Acad. Sci. USA 91, 10370–10374 (1994).

    CAS  PubMed  Google Scholar 

  8. Bosshard, H.R. Molecular recognition by induced fit: how fit is the concept? News Physiol. Sci. 16, 171–173 (2001).

    CAS  PubMed  Google Scholar 

  9. Berger, C. et al. Antigen recognition by conformational selection. FEBS Lett. 450, 149–153 (1999).

    CAS  PubMed  Google Scholar 

  10. Leder, L. et al. Spectroscopic, calorimetric, and kinetic demonstration of conformational adaptation in peptide-antibody recognition. Biochemistry 34, 16509–16518 (1995).

    CAS  PubMed  Google Scholar 

  11. Kumar, S., Ma, B., Tsai, C.J., Sinha, N. & Nussinov, R. Folding and binding cascades: dynamic landscapes and population shifts. Protein Sci. 9, 10–19 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Miller, D.W. & Dill, K.A. Ligand binding to proteins: the binding landscape model. Protein Sci. 6, 2166–2179 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Dill, K.A. & Chan, H.S. From Levinthal to pathways to funnels. Nat. Struct. Biol. 4, 10–19 (1997).

    CAS  PubMed  Google Scholar 

  14. Ma, B., Shatsky, M., Wolfson, H.J. & Nussinov, R. Multiple diverse ligands binding at a single protein site: a matter of pre-existing populations. Protein Sci. 11, 184–197 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Greenleaf, W.J., Woodside, M.T. & Block, S.M. High-resolution, single-molecule measurements of biomolecular motion. Annu. Rev. Biophys. Biomol. Struct. 36, 171–190 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Parak, F.G. Proteins in action: the physics of structural fluctuations and conformational changes. Curr. Opin. Struct. Biol. 13, 552–557 (2003).

    CAS  PubMed  Google Scholar 

  17. Hinterdorfer, P. & Dufrene, Y.F. Detection and localization of single molecular recognition events using atomic force microscopy. Nat. Methods 3, 347–355 (2006).

    CAS  PubMed  Google Scholar 

  18. Busenlehner, L.S. & Armstrong, R.N. Insights into enzyme structure and dynamics elucidated by amide H/D exchange mass spectrometry. Arch. Biochem. Biophys. 433, 34–46 (2005).

    CAS  PubMed  Google Scholar 

  19. Palmer, A.G. III. Nmr probes of molecular dynamics: overview and comparison with other techniques. Annu. Rev. Biophys. Biomol. Struct. 30, 129–155 (2001).

    CAS  PubMed  Google Scholar 

  20. Tobi, D. & Bahar, I. Structural changes involved in protein binding correlate with intrinsic motions of proteins in the unbound state. Proc. Natl. Acad. Sci. USA 102, 18908–18913 (2005).

    CAS  PubMed  Google Scholar 

  21. Keskin, O. Binding induced conformational changes of proteins correlate with their intrinsic fluctuations: a case study of antibodies. BMC Struct. Biol. 7, 31 (2007).

    PubMed  PubMed Central  Google Scholar 

  22. Grunberg, R., Leckner, J. & Nilges, M. Complementarity of structure ensembles in protein-protein binding. Structure 12, 2125–2136 (2004).

    CAS  PubMed  Google Scholar 

  23. Austin, R.H., Beeson, K.W., Eisenstein, L., Frauenfelder, H. & Gunsalus, I.C. Dynamics of ligand binding to myoglobin. Biochemistry 14, 5355–5373 (1975).

    CAS  PubMed  Google Scholar 

  24. Schotte, F. et al. Watching a protein as it functions with 150-ps time-resolved x-ray crystallography. Science 300, 1944–1947 (2003).

    CAS  PubMed  Google Scholar 

  25. Vos, M.H. Ultrafast dynamics of ligands within heme proteins. Biochim. Biophys. Acta 1777, 15–31 (2008).

    CAS  PubMed  Google Scholar 

  26. Lee, A.Y., Gulnik, S.V. & Erickson, J.W. Conformational switching in an aspartic proteinase. Nat. Struct. Biol. 5, 866–871 (1998).

    CAS  PubMed  Google Scholar 

  27. Henzler-Wildman, K.A. et al. Intrinsic motions along an enzymatic reaction trajectory. Nature 450, 838–844 (2007). This study provides experimental support from X-ray crystallography, NMR and single-molecule fluorescence that adenylate kinase fluctuates between open and closed states in the absence of ligand.

    CAS  PubMed  Google Scholar 

  28. Muller, Y.A., Kelley, R.F. & de Vos, A.M. 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. 7, 1106–1115 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. James, L.C., Roversi, P. & Tawfik, D.S. Antibody multispecificity mediated by conformational diversity. Science 299, 1362–1367 (2003).

    CAS  PubMed  Google Scholar 

  30. Hanes, J., Jermutus, L., Weber-Bornhauser, S., Bosshard, H.R. & Pluckthun, A. Ribosome display efficiently selects and evolves high-affinity antibodies in vitro from immune libraries. Proc. Natl. Acad. Sci. USA 95, 14130–14135 (1998).

    CAS  PubMed  Google Scholar 

  31. Stella, L. et al. Flexibility of helix 2 in the human glutathione transferase P1–1. time-resolved fluorescence spectroscopy. J. Biol. Chem. 273, 23267–23273 (1998).

    CAS  PubMed  Google Scholar 

  32. Xu, J. & Root, D.D. Conformational selection during weak binding at the actin and myosin interface. Biophys. J. 79, 1498–1510 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Cao, Y., Musah, R.A., Wilcox, S.K., Goodin, D.B. & McRee, D.E. Protein conformer selection by ligand binding observed with crystallography. Protein Sci. 7, 72–78 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Mittermaier, A. & Kay, L.E. New tools provide new insights in NMR studies of protein dynamics. Science 312, 224–228 (2006).

    CAS  PubMed  Google Scholar 

  35. Cavalli, A., Salvatella, X., Dobson, C.M. & Vendruscolo, M. Protein structure determination from NMR chemical shifts. Proc. Natl. Acad. Sci. USA 104, 9615–9620 (2007).

    CAS  PubMed  Google Scholar 

  36. Vallurupalli, P., Hansen, D.F., Stollar, E., Meirovitch, E. & Kay, L.E. Measurement of bond vector orientations in invisible excited states of proteins. Proc. Natl. Acad. Sci. USA 104, 18473–18477 (2007).

    CAS  PubMed  Google Scholar 

  37. Igumenova, T.I., Brath, U., Akke, M. & Palmer, A.G. III. Characterization of chemical exchange using residual dipolar coupling. J. Am. Chem. Soc. 129, 13396–13397 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Hansen, D.F., Vallurupalli, P. & Kay, L.E. Using relaxation dispersion NMR spectroscopy to determine structures of excited, invisible protein states. J. Biomol. NMR 41, 113–120 (2008).

    CAS  PubMed  Google Scholar 

  39. Beach, H., Cole, R., Gill, M.L. & Loria, J.P. Conservation of mus-ms enzyme motions in the apo- and substrate-mimicked state. J. Am. Chem. Soc. 127, 9167–9176 (2005).

    CAS  PubMed  Google Scholar 

  40. Wolf-Watz, M. et al. Linkage between dynamics and catalysis in a thermophilic-mesophilic enzyme pair. Nat. Struct. Mol. Biol. 11, 945–949 (2004).

    CAS  PubMed  Google Scholar 

  41. Boehr, D.D., McElheny, D., Dyson, H.J. & Wright, P.E. The dynamic energy landscape of dihydrofolate reductase catalysis. Science 313, 1638–1642 (2006). This study suggests that every functional intermediate of dihydrofolate reductase fluctuates into a higher energy conformation that is structurally similar to the next and/or previous complex in the catalytic cycle.

    CAS  PubMed  Google Scholar 

  42. McElheny, D., Schnell, J.R., Lansing, J.C., Dyson, H.J. & Wright, P.E. Defining the role of active-site loop fluctuations in dihydrofolate reductase catalysis. Proc. Natl. Acad. Sci. USA 102, 5032–5037 (2005).

    CAS  PubMed  Google Scholar 

  43. Hanson, J.A. et al. Illuminating the mechanistic roles of enzyme conformational dynamics. Proc. Natl. Acad. Sci. USA 104, 18055–18060 (2007).

    CAS  PubMed  Google Scholar 

  44. Eisenmesser, E.Z. et al. Intrinsic dynamics of an enzyme underlies catalysis. Nature 438, 117–121 (2005).

    CAS  PubMed  Google Scholar 

  45. Antikainen, N.M., Smiley, R.D., Benkovic, S.J. & Hammes, G.G. Conformation coupled enzyme catalysis: single-molecule and transient kinetics investigation of dihydrofolate reductase. Biochemistry 44, 16835–16843 (2005).

    CAS  PubMed  Google Scholar 

  46. Boehr, D.D., Dyson, H.J. & Wright, P.E. Conformational relaxation following hydride transfer plays a limiting role in dihydrofolate reductase catalysis. Biochemistry 47, 9227–9233 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Kitahara, R. et al. High pressure NMR reveals active-site hinge motion of folate-bound Escherichia coli dihydrofolate reductase. Biochemistry 39, 12789–12795 (2000).

    CAS  PubMed  Google Scholar 

  48. Mauldin, R.V., Carroll, M.J. & Lee, A.L. Dynamic dysfunction in dihydrofolate reductase results from antifolate drug binding: modulation of dynamics within a structural state. Structure 17, 386–394 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Tang, C., Schwieters, C.D. & Clore, G.M. Open-to-closed transition in apo maltose-binding protein observed by paramagnetic NMR. Nature 449, 1078–1082 (2007).

    CAS  PubMed  Google Scholar 

  50. Lu, Z.L., Coetsee, M., White, C.D. & Millar, R.P. Structural determinants for ligand-receptor conformational selection in a peptide G protein-coupled receptor. J. Biol. Chem. 282, 17921–17929 (2007).

    CAS  PubMed  Google Scholar 

  51. Fenwick, R. et al. Solution structure and dynamics of the small GTPase RalB in its active conformation: significance for effector protein binding. Biochemistry 48, 2192–2206 (2009).

    CAS  PubMed  Google Scholar 

  52. Saitoh, T. et al. Tom20 recognizes mitochondrial presequences through dynamic equilibrium among multiple bound states. EMBO J. 26, 4777–4787 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Brath, U. & Akke, M. Differential responses of the backbone and side chain conformational dynamics in FKBP12 upon binding the transition state analog FK506: implications for transition state stabilization and target protein recognition. J. Mol. Biol. 387, 233–244 (2009).

    CAS  PubMed  Google Scholar 

  54. Keramisanou, D. et al. Disorder-order folding transitions underlie catalysis in the helicase motor of SecA. Nat. Struct. Mol. Biol. 13, 594–602 (2006).

    CAS  PubMed  Google Scholar 

  55. Gsponer, J. et al. A coupled equilibrium shift mechanism in calmodulin-mediated signal transduction. Structure 16, 736–746 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Nevo, R. et al. A molecular switch between alternative conformational states in the complex of Ran and importin beta1. Nat. Struct. Biol. 10, 553–557 (2003).

    CAS  PubMed  Google Scholar 

  57. Junker, J.P., Ziegler, F. & Rief, M. Ligand-dependent equilibrium fluctuations of single calmodulin molecules. Science 323, 633–637 (2009).

    CAS  PubMed  Google Scholar 

  58. Koglin, A. et al. Conformational switches modulate protein interactions in peptide antibiotic synthetases. Science 312, 273–276 (2006).

    CAS  PubMed  Google Scholar 

  59. Koglin, A. et al. Structural basis for the selectivity of the external thioesterase of the surfactin synthetase. Nature 454, 907–911 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Lange, O.F. et al. Recognition dynamics up to microseconds revealed from an RDC-derived ubiquitin ensemble in solution. Science 320, 1471–1475 (2008). This report presents an NMR-derived conformational ensemble of ubiquitin that encompasses all the crystallographically determined conformations of ubiquitin.

    CAS  PubMed  Google Scholar 

  61. Kalodimos, C. et al. Structure and flexibility adaptation in nonspecific and specific protein-DNA complexes. Science 305, 386–389 (2004). This study compares the structure and dynamics of the lac repressor headpiece when bound to cognate versus noncognate DNA, and demonstrates that the underlying energy landscapes are distinct.

    CAS  PubMed  Google Scholar 

  62. Zhang, Q., Stelzer, A.C., Fisher, C.K. & Al-Hashimi, H.M. Visualizing spatially correlated dynamics that directs RNA conformational transitions. Nature 450, 1263–1267 (2007). This study demonstrates that TAR RNA fluctuates into multiple “bound” conformations in the absence of ligands.

    CAS  PubMed  Google Scholar 

  63. Al-Hashimi, H.M. & Walter, N.G. RNA dynamics: it is about time. Curr. Opin. Struct. Biol. 18, 321–329 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Mittag, T. & Forman-Kay, J.D. Atomic-level characterization of disordered protein ensembles. Curr. Opin. Struct. Biol. 17, 3–14 (2007).

    CAS  PubMed  Google Scholar 

  65. Lakomek, N.A. et al. Residual dipolar couplings as a tool to study molecular recognition of ubiquitin. Biochem. Soc. Trans. 36, 1433–1437 (2008).

    CAS  PubMed  Google Scholar 

  66. Clore, G.M., Tang, C. & Iwahara, J. Elucidating transient macromolecular interactions using paramagnetic relaxation enhancement. Curr. Opin. Struct. Biol. 17, 603–616 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Lindorff-Larsen, K., Best, R.B., Depristo, M.A., Dobson, C.M. & Vendruscolo, M. Simultaneous determination of protein structure and dynamics. Nature 433, 128–132 (2005).

    CAS  PubMed  Google Scholar 

  68. Lipari, G. & Szabo, A. Nuclear magnetic resonance relaxation in nucleic acid fragments: models for internal motion. Biochemistry 20, 6250–6256 (1981).

    CAS  PubMed  Google Scholar 

  69. Lakomek, N.A., Carlomagno, T., Becker, S., Griesinger, C. & Meiler, J. A thorough dynamic interpretation of residual dipolar couplings in ubiquitin. J. Biomol. NMR 34, 101–115 (2006).

    CAS  PubMed  Google Scholar 

  70. Esler, W.P. et al. Alzheimer's disease amyloid propagation by a template-dependent dock-lock mechanism. Biochemistry 39, 6288–6295 (2000).

    CAS  PubMed  Google Scholar 

  71. Tessier, P.M. & Lindquist, S. Prion recognition elements govern nucleation, strain specificity and species barriers. Nature 447, 556–561 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Kalodimos, C., Boelens, R. & Kaptein, R. Toward an integrated model of protein−DNA recognition as inferred from NMR studies on the lac repressor system. Chem. Rev. 104, 3567–3586 (2004).

    CAS  PubMed  Google Scholar 

  73. von Hippel, P.H. & Berg, O.G. Facilitated target location in biological systems. J. Biol. Chem. 264, 675–678 (1989).

    CAS  PubMed  Google Scholar 

  74. Gorman, J. & Greene, E.C. Visualizing one-dimensional diffusion of proteins along DNA. Nat. Struct. Mol. Biol. 15, 768–774 (2008).

    CAS  PubMed  Google Scholar 

  75. Zhang, Q., Stelzer, A., Fisher, C. & Al-Hashimi, H. Visualizing spatially correlated dynamics that directs RNA conformational transitions. Nature 450, 1263–1267 (2007).

    CAS  PubMed  Google Scholar 

  76. Monod, J., Wyman, J. & Changeux, J.P. On the nature of allosteric transitions: A plausible model. J. Mol. Biol. 12, 88–118 (1965).

    CAS  PubMed  Google Scholar 

  77. Kantrowitz, E.R. & Lipscomb, W.N. Escherichia coli aspartate transcarbamoylase: the molecular basis for a concerted allosteric transition. Trends Biochem. Sci. 15, 53–59 (1990).

    CAS  PubMed  Google Scholar 

  78. Velyvis, A., Yang, Y.R., Schachman, H.K. & Kay, L.E. A solution NMR study showing that active site ligands and nucleotides directly perturb the allosteric equilibrium in aspartate transcarbamoylase. Proc. Natl. Acad. Sci. USA 104, 8815–8820 (2007).

    CAS  PubMed  Google Scholar 

  79. Velyvis, A., Schachman, H.K. & Kay, L.E. Application of methyl-TROSY NMR to test allosteric models describing effects of nucleotide binding to aspartate transcarbamoylase. J. Mol. Biol. 387, 540–547 (2009).

    CAS  PubMed  Google Scholar 

  80. Gunasekaran, K., Ma, B. & Nussinov, R. Is allostery an intrinsic property of all dynamic proteins? Proteins 57, 433–443 (2004).

    CAS  PubMed  Google Scholar 

  81. Volkman, B.F., Lipson, D., Wemmer, D.E. & Kern, D. Two-state allosteric behavior in a single-domain signaling protein. Science 291, 2429–2433 (2001).

    CAS  PubMed  Google Scholar 

  82. Yao, X., Rosen, M.K. & Gardner, K.H. Estimation of the available free energy in a LOV2-J alpha photoswitch. Nat. Chem. Biol. 4, 491–497 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Li, P., Martins, I.R., Amarasinghe, G.K. & Rosen, M.K. Internal dynamics control activation and activity of the autoinhibited Vav DH domain. Nat. Struct. Mol. Biol. 15, 613–618 (2008). This study presents a linear correlation between biological activity and the population of the Vav DH higher energy conformation. This provides both structural and functional evidence for the involvement of a higher energy conformation in biological function.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Boehr, D.D., Dyson, H.J. & Wright, P.E. An NMR perspective on enzyme dynamics. Chem. Rev. 106, 3055–3079 (2006).

    CAS  PubMed  Google Scholar 

  85. Lee, G.M. & Craik, C.S. Trapping moving targets with small molecules. Science 324, 213–215 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Bursavich, M.G. & Rich, D.H. Designing non-peptide peptidomimetics in the 21st century: inhibitors targeting conformational ensembles. J. Med. Chem. 45, 541–558 (2002).

    CAS  PubMed  Google Scholar 

  87. Totrov, M. & Abagyan, R. Flexible ligand docking to multiple receptor conformations: a practical alternative. Curr. Opin. Struct. Biol. 18, 178–184 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Andrusier, N., Mashiach, E., Nussinov, R. & Wolfson, H.J. Principles of flexible protein-protein docking. Proteins 73, 271–289 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Chaudhury, S. & Gray, J.J. Conformer selection and induced fit in flexible backbone protein-protein docking using computational and NMR ensembles. J. Mol. Biol. 381, 1068–1087 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Lindsley, C.W. & Emmitte, K.A. Recent progress in the discovery and development of negative allosteric modulators of mGluR5. Curr. Opin. Drug Discov. Devel. 12, 446–457 (2009).

    CAS  PubMed  Google Scholar 

  91. Frederick, K.K., Marlow, M.S., Valentine, K.G. & Wand, A.J. Conformational entropy in molecular recognition by proteins. Nature 448, 325–329 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Rothlisberger, D. et al. Kemp elimination catalysts by computational enzyme design. Nature 453, 190–195 (2008).

    PubMed  Google Scholar 

  93. Jiang, L. et al. De novo computational design of retro-aldol enzymes. Science 319, 1387–1391 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Hilvert, D. Critical analysis of antibody catalysis. Annu. Rev. Biochem. 69, 751–793 (2000).

    CAS  PubMed  Google Scholar 

  95. Pauling, L. & Delbruck, M. The nature of the intermolecular forces operative in biological processes. Science 92, 77–79 (1940).

    CAS  PubMed  Google Scholar 

  96. James, L.C. & Tawfik, D.S. Conformational diversity and protein evolution—a 60-year-old hypothesis revisited. Trends Biochem. Sci. 28, 361–368 (2003).

    CAS  PubMed  Google Scholar 

  97. Tokuriki, N. & Tawfik, D.S. Protein dynamism and evolvability. Science 324, 203–207 (2009).

    CAS  PubMed  Google Scholar 

  98. Wedemayer, G.J., Patten, P.A., Wang, L.H., Schultz, P.G. & Stevens, R.C. Structural insights into the evolution of an antibody combining site. Science 276, 1665–1669 (1997).

    CAS  PubMed  Google Scholar 

  99. Weikl, T. & Von Deuster, C. Selected-fit versus induced-fit protein binding: kinetic differences and mutational analysis. Proteins 75, 104–110 (2009).

    CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the US National Institutes of Health (NIH grants GM75995 and CA96865 to P.E.W.) and by the Skaggs Institute for Chemical Biology. This project has been funded in whole or in part with federal funds from the National Cancer Institute, NIH, under contract number N01-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government. This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.

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Boehr, D., Nussinov, R. & Wright, P. The role of dynamic conformational ensembles in biomolecular recognition. Nat Chem Biol 5, 789–796 (2009). https://doi.org/10.1038/nchembio.232

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