Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Intrinsic motions along an enzymatic reaction trajectory

Nature volume 450, pages 838–844 (2007)Cite this article

Abstract

The mechanisms by which enzymes achieve extraordinary rate acceleration and specificity have long been of key interest in biochemistry. It is generally recognized that substrate binding coupled to conformational changes of the substrate–enzyme complex aligns the reactive groups in an optimal environment for efficient chemistry. Although chemical mechanisms have been elucidated for many enzymes, the question of how enzymes achieve the catalytically competent state has only recently become approachable by experiment and computation. Here we show crystallographic evidence for conformational substates along the trajectory towards the catalytically competent ‘closed’ state in the ligand-free form of the enzyme adenylate kinase. Molecular dynamics simulations indicate that these partially closed conformations are sampled in nanoseconds, whereas nuclear magnetic resonance and single-molecule fluorescence resonance energy transfer reveal rare sampling of a fully closed conformation occurring on the microsecond-to-millisecond timescale. Thus, the larger-scale motions in substrate-free adenylate kinase are not random, but preferentially follow the pathways that create the configuration capable of proficient chemistry. Such preferred directionality, encoded in the fold, may contribute to catalysis in many enzymes.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Kinetic model and X-ray structure of Aquifex Adk.
Figure 2: Conformational substates of ligand-free Aquifex Adk detected in the crystal structure.
Figure 3: Characterization of millisecond dynamics of Aquifex Adk in solution by NMR.
Figure 4: Dynamics of Aquifex Adk computed by molecular dynamics simulations and normal mode analysis.
Figure 5: Opening and closing of Aquifex Adk in solution by single-molecule FRET.

Similar content being viewed by others

References

  1. 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 

  2. McCammon, J. A., Gelin, B. R. & Karplus, M. Dynamics of folded proteins. Nature 267, 585–590 (1977)

    ADS  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)

    ADS  CAS  PubMed  Google Scholar 

  4. Frauenfelder, H., McMahon, B. H. & Fenimore, P. W. Myoglobin: the hydrogen atom of biology and a paradigm of complexity. Proc. Natl Acad. Sci. USA 100, 8615–8617 (2003)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  5. Levinthal, C. Are there pathways for protein folding. J. Chim. Phys. Phys.-Chim. Biol. 65, 44–45 (1968)

    ADS  Google Scholar 

  6. Bryngelson, J. D., Onuchic, J. N., Socci, N. D. & Wolynes, P. G. Funnels, pathways, and the energy landscape of protein folding: a synthesis. Proteins 21, 167–195 (1995)

    CAS  PubMed  Google Scholar 

  7. Dobson, C. M., Sali, A. & Karplus, M. Protein folding: a perspective from theory and experiment. Angew. Chem. Int. Ed. 37, 868–893 (1998)

    Google Scholar 

  8. Williams, J. C. & McDermott, A. E. Dynamics of the flexible loop of triosephosphate isomerase: the loop motion is not ligand gated. Biochemistry 34, 8309–8319 (1995)

    CAS  PubMed  Google Scholar 

  9. Boehr, D. D., McElheny, D., Dyson, H. J. & Wright, P. E. The dynamic energy landscape of dihydrofolate reductase catalysis. Science 313, 1638–1642 (2006)

    ADS  CAS  PubMed  Google Scholar 

  10. Palmer, A. G. NMR characterization of the dynamics of biomacromolecules. Chem. Rev. 104, 3623–3640 (2004)

    CAS  PubMed  Google Scholar 

  11. Cui, Q. & Karplus, M. Catalysis and specificity in enzymes: a study of triosephosphate isomerase and comparison with methyl glyoxal synthase. Adv. Protein Chem. 66, 315–372 (2003)

    CAS  PubMed  Google Scholar 

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

    ADS  CAS  PubMed  Google Scholar 

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

    CAS  Google Scholar 

  14. Blanchard, S. C., Gonzalez, R. L., Kim, H. D., Chu, S. & Puglisi, J. D. tRNA selection and kinetic proofreading in translation. Nature Struct. Mol. Biol. 11, 1008–1014 (2004)

    CAS  Google Scholar 

  15. Ha, T. et al. Single-molecule fluorescence spectroscopy of enzyme conformational dynamics and cleavage mechanism. Proc. Natl Acad. Sci. USA 96, 893–898 (1999)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  16. Myong, S., Stevens, B. C. & Ha, T. Bridging conformational dynamics and function using single-molecule spectroscopy. Structure 14, 633–643 (2006)

    CAS  PubMed  Google Scholar 

  17. Rothwell, P. J. et al. Multiparameter single-molecule fluorescence spectroscopy reveals heterogeneity of HIV-1 reverse transcriptase: primer/template complexes. Proc. Natl Acad. Sci. USA 100, 1655–1660 (2003)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  18. Schuler, B., Lipman, E. A. & Eaton, W. A. Probing the free-energy surface for protein folding with single-molecule fluorescence spectroscopy. Nature 419, 743–747 (2002)

    ADS  CAS  PubMed  Google Scholar 

  19. Zhang, Z., Rajagopalan, P. T. R., Selzer, T., Benkovic, S. J. & Hammes, G. G. Single-molecule and transient kinetics investigation of the interaction of dihydrofolate reductase with NADPH and dihydrofolate. Proc. Natl Acad. Sci. USA 101, 2764–2769 (2004)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  20. Vonrhein, C., Schlauderer, G. J. & Schulz, G. E. Movie of the structural changes during a catalytic cycle of nucleoside monophosphate kinases. Structure 3, 483–490 (1995)

    CAS  PubMed  Google Scholar 

  21. Müller, C. W., Schlauderer, G. J., Reinstein, J. & Schulz, G. E. Adenylate kinase motions during catalysis: an energetic counterweight balancing substrate binding. Structure 4, 147–156 (1996)

    PubMed  Google Scholar 

  22. Henzler-Wildman, K. A. et al. A hierarchy of timescales in protein dynamics is linked to enzyme catalysis. Nature doi: 10.1038/nature06407 (this issue).

  23. Müller, C. W. & Schulz, G. E. Structure of the complex between adenylate kinase from Escherichia coli and the inhibitor Ap5A refined at 1.9 Å resolution. A model for a catalytic transition state. J. Mol. Biol. 224, 159–177 (1992)

    PubMed  Google Scholar 

  24. Blaszczyk, J., Li, Y., Yan, H. G. & Ji, X. H. Crystal structure of unligated guanylate kinase from yeast reveals GMP-induced conformational changes. J. Mol. Biol. 307, 247–257 (2001)

    CAS  PubMed  Google Scholar 

  25. Faber, H. R. & Matthews, B. W. A mutant T4 lysozyme displays 5 different crystal conformations. Nature 348, 263–266 (1990)

    ADS  CAS  PubMed  Google Scholar 

  26. Gardberg, A., Shuvalova, L., Monnerjahn, C., Konrad, M. & Lavie, A. Structural basis for the dual thymidine and thymidylate kinase activity of herpes thymidine kinases. Structure 11, 1265–1277 (2003)

    CAS  PubMed  Google Scholar 

  27. Odintsov, S. G., Sabala, I., Bourenkov, G., Rybin, V. & Bochtler, M. Substrate access to the active sites in aminopeptidase T, a representative of a new metallopeptidase clan. J. Mol. Biol. 354, 403–412 (2005)

    CAS  PubMed  Google Scholar 

  28. Gerstein, M., Schulz, G. & Chothia, C. Domain closure in adenylate kinase — joints on either side of 2 helices close like neighboring fingers. J. Mol. Biol. 229, 494–501 (1993)

    CAS  PubMed  Google Scholar 

  29. Maragakis, P. & Karplus, M. Large amplitude conformational change in proteins explored with a plastic network model: adenylate kinase. J. Mol. Biol. 352, 807–822 (2005)

    CAS  PubMed  Google Scholar 

  30. Karplus, M. & Kushick, J. N. Method for estimating the configurational entropy of macromolecules. Macromolecules 14, 325–332 (1981)

    ADS  CAS  Google Scholar 

  31. Ma, J. & Karplus, M. Ligand-induced conformational changes in ras p21: a normal mode and energy minimization analysis. J. Mol. Biol. 274, 114–131 (1997)

    CAS  PubMed  Google Scholar 

  32. Bahar, I. & Rader, A. J. Coarse-grained normal mode analysis in structural biology. Curr. Opin. Struct. Biol. 15, 586–592 (2005)

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Miyashita, O., Onuchic, J. N. & Wolynes, P. G. Nonlinear elasticity, proteinquakes, and the energy landscapes of functional transitions in proteins. Proc. Natl Acad. Sci. USA 100, 12570–12575 (2003)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  34. Lou, H. & Cukier, R. I. Molecular dynamics of apo-adenylate kinase: a principal component analysis. J. Phys. Chem. B 110, 12796–12808 (2006)

    CAS  PubMed  Google Scholar 

  35. Ha, T. et al. Probing the interaction between two single molecules: fluorescence resonance energy transfer between a single donor and a single acceptor. Proc. Natl Acad. Sci. USA 93, 6264–6268 (1996)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  36. Rhoads, D. G. & Lowenstein, J. M. Initial velocity and equilibrium kinetics of myokinase. J. Biol. Chem. 243, 3963–3972 (1968)

    CAS  PubMed  Google Scholar 

  37. Nie, S., Chiu, D. T. & Zare, R. N. Probing individual molecules with confocal fluorescence microscopy. Science 266, 1018–1021 (1994)

    ADS  CAS  PubMed  Google Scholar 

  38. Margittai, M. et al. Single-molecule fluorescence resonance energy transfer reveals a dynamic equilibrium between closed and open conformations of syntaxin 1. Proc. Natl Acad. Sci. USA 100, 15516–15521 (2003)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  39. Iwahara, J., Tang, C. & Clore, G. M. Practical aspects of 1H transverse paramagnetic relaxation enhancement measurements on macromolecules. J. Magn. Reson. 184, 185–195 (2007)

    ADS  CAS  PubMed  Google Scholar 

  40. Bruice, T. C. Computational approaches: reaction trajectories, structures, and atomic motions. Enzyme reactions and proficiency. Chem. Rev. 106, 3119–3139 (2006)

    CAS  PubMed  Google Scholar 

  41. Hammes-Schiffer, S. & Benkovic, S. J. Relating protein motion to catalysis. Annu. Rev. Biochem. 75, 519–541 (2006)

    CAS  PubMed  Google Scholar 

  42. Nagel, Z. D. & Klinman, J. P. Tunneling and dynamics in enzymatic hydride transfer. Chem. Rev. 106, 3095–3118 (2006)

    CAS  PubMed  Google Scholar 

  43. Vendruscolo, M. & Dobson, C. M. Dynamic visions of enzymatic reactions. Science 313, 1586–1587 (2006)

    CAS  PubMed  Google Scholar 

  44. Karplus, M. & Mccammon, J. A. The internal dynamics of globular-proteins. Crit. Rev. Biochem. 9, 293–349 (1981)

    CAS  Google Scholar 

  45. Kuriyan, J. & Weis, W. I. Rigid protein motion as a model for crystallographic temperature factors. Proc. Natl Acad. Sci. USA 88, 2773–2777 (1991)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  46. Loria, J. P., Rance, M. & Palmer, A. G. A. TROSY CPMG sequence for characterizing chemical exchange in large proteins. J. Biomol. NMR 15, 151–155 (1999)

    CAS  PubMed  Google Scholar 

  47. Mulder, F. A. A., Mittermaier, A., Hon, B., Dahlquist, F. W. & Kay, L. E. Studying excited states of proteins by NMR spectroscopy. Nature Struct. Biol. 8, 932–935 (2001)

    CAS  PubMed  Google Scholar 

  48. Brooks, B. R. et al. CHARMM — a program for macromolecular energy, minimization, and dynamics calculations. J. Comput. Chem. 4, 187–217 (1983)

    CAS  Google Scholar 

  49. Otwinowski, Z. & Minor, W. Processing of X-ray diffraction data collected in oscillating mode. Methods Enzymol. 276, 307–326 (1997)

    CAS  PubMed  Google Scholar 

  50. Navaza, J. AMORE — an automated package for molecular replacement. Acta Crystallogr. A 50, 157–163 (1994)

    Google Scholar 

  51. Collaborative Computational Project, 4. The CCP4 Suite — programs for protein crystallography. Acta Crystallogr. D 50, 760–763 (1994)

    Google Scholar 

  52. Jones, T. A., Zou, J. Y., Cowan, S. W. & Kjeldgaard, M. Improved methods for building protein models in electron-density maps and the location of errors in these models. Acta Crystallogr. A 47, 110–119 (1991)

    Article  PubMed  Google Scholar 

  53. Brunger, A. T. et al. Crystallography & NMR system: a new software suite for macromolecular structure determination. Acta Crystallogr. D 54, 905–921 (1998)

    CAS  PubMed  Google Scholar 

  54. Immirzi, A. in Crystallographic Computing Techniques (ed. Ahmed, F. R.) 399–412 (Munksgaard, Copenhagen, 1976)

    Google Scholar 

  55. Murshudov, G. N., Vagin, A. A. & Dodson, E. J. Refinement of macromolecular structures by the maximum-likelihood method. Acta Crystallogr. D 53, 240–255 (1997)

    Article  CAS  PubMed  Google Scholar 

  56. Read, R. J. Pushing the boundaries of molecular replacement with maximum likelihood. Acta Crystallogr. D 57, 1373–1382 (2001)

    CAS  PubMed  Google Scholar 

  57. Terwilliger, T. C. & Berendzen, J. Automated MAD and MIR structure solution. Acta Crystallogr. D 55, 849–861 (1999)

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Terwilliger, T. C. Maximum-likelihood density modification. Acta Crystallogr. D 56, 965–972 (2000)

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Read, R. J. Improved Fourier coefficients for maps using phases from partial structures with errors. Acta Crystallogr. A 42, 140–149 (1986)

    Google Scholar 

  60. Perrakis, A., Morris, R. & Lamzin, V. S. Automated protein model building combined with iterative structure refinement. Nature Struct. Biol. 6, 458–463 (1999)

    CAS  PubMed  Google Scholar 

  61. Reddy, V. et al. Effective electron-density map improvement and structure validation on a Linux multi-CPU web cluster: the TB structural genomics consortium bias removal Web service. Acta Crystallogr. D 59, 2200–2210 (2003)

    PubMed  Google Scholar 

  62. Schomaker, V. & Trueblood, K. N. On rigid-body motion of molecules in crystals. Acta Crystallogr. B 24, 63–76 (1968)

    CAS  Google Scholar 

  63. Emsley, P. & Cowtan, K. Coot: model-building tools for molecular graphics. Acta Crystallogr. D 60, 2126–2132 (2004)

    PubMed  Google Scholar 

  64. Howlin, B. & Butler, S. A. Moss, D. S., Harris, G. W. & Driessen, H. P. C. TLSANL — TLS parameter-analysis program for segmented anisotropic refinement of macromolecular structures. J. Appl. Cryst. 26, 622–624 (1993)

    Google Scholar 

  65. Carver, J. P. & Richards, R. E. A general two-site solution for the chemical exchange produced dependence of T2 upon the Carr–Purcell pulse separation. J. Magn. Reson. 6, 89–105 (1972)

    ADS  CAS  Google Scholar 

  66. Riddles, P. W., Blakeley, R. L. & Zerner, B. Ellman’s reagent: 5,5′-dithiobis(2-nitrobenzoic acid) — a reexamination. Anal. Biochem. 94, 75–81 (1979)

    CAS  PubMed  Google Scholar 

  67. Battiste, J. L. & Wagner, G. Utilization of site-directed spin labeling and high-resolution heteronuclear nuclear magnetic resonance for global fold determination of large proteins with limited nuclear overhauser effect data. Biochemistry 39, 5355–5365 (2000)

    CAS  PubMed  Google Scholar 

  68. Donaldson, L. W. et al. Structural characterization of proteins with an attached ATCUN motif by paramagnetic relaxation enhancement NMR spectroscopy. J. Am. Chem. Soc. 123, 9843–9847 (2001)

    CAS  PubMed  Google Scholar 

  69. Solomon, I. & Bloembergen, N. Nuclear magnetic interactions in the HF molecule. J. Chem. Phys. 25, 261–266 (1956)

    ADS  CAS  Google Scholar 

  70. Brooks, C. L. & Karplus, M. Deformable stochastic boundaries in molecular-dynamics. J. Chem. Phys. 79, 6312–6325 (1983)

    ADS  CAS  Google Scholar 

  71. Brunger, A., Brooks, C. L. & Karplus, M. Stochastic boundary-conditions for molecular-dynamics simulations of ST2 water. Chem. Phys. Lett. 105, 495–500 (1984)

    ADS  Google Scholar 

  72. Price, D. J. & Brooks, C. L. A modified TIP3P water potential for simulation with Ewald summation. J. Chem. Phys. 121, 10096–10103 (2004)

    ADS  CAS  PubMed  Google Scholar 

  73. MacKerell, A. D. et al. All-atom empirical potential for molecular modeling and dynamics studies of proteins. J. Phys. Chem. B 102, 3586–3616 (1998)

    CAS  PubMed  Google Scholar 

  74. MacKerell, A. D., Feig, M. & Brooks, C. L. Extending the treatment of backbone energetics in protein force fields: limitations of gas-phase quantum mechanics in reproducing protein conformational distributions in molecular dynamics simulations. J. Comput. Chem. 25, 1400–1415 (2004)

    CAS  PubMed  Google Scholar 

  75. Ryckaert, J. P., Ciccotti, G. & Berendsen, H. J. C. Numerical-integration of cartesian equations of motion of a system with constraints — molecular-dynamics of N-alkanes. J. Comput. Phys. 23, 327–341 (1977)

    ADS  CAS  Google Scholar 

  76. Lazaridis, T. & Karplus, M. Effective energy function for proteins in solution. Proteins 35, 133–152 (1999)

    CAS  PubMed  Google Scholar 

  77. Ichiye, T. & Karplus, M. Collective motions in proteins — a covariance analysis of atomic fluctuations in molecular-dynamics and normal mode simulations. Proteins 11, 205–217 (1991)

    CAS  PubMed  Google Scholar 

  78. Lakowicz, J. R. Principles of Fluorescence Spectroscopy page 446 (Springer, New York, 2006)

    Google Scholar 

  79. Zondervan, R., Kulzer, F., Orlinskii, S. B. & Orrit, M. Photoblinking of rhodamine 6G in poly(vinyl alcohol): radical dark state formed through the triplet. J. Phys. Chem. A 107, 6770–6776 (2003)

    CAS  Google Scholar 

  80. Vosch, T. et al. Probing Forster type energy pathways in a first generation rigid dendrimer bearing two perylene imide chromophores. J. Phys. Chem. A 107, 6920–6931 (2003)

    CAS  Google Scholar 

  81. Hübner, C. G. et al. Photon antibunching and collective effects in the fluorescence of single bichromophoric molecules. Phys. Rev. Lett. 91, 093903 (2003)

    ADS  PubMed  Google Scholar 

  82. Antonik, M., Felekyan, S., Gaiduk, A. & Seidel, C. A. M. Separating structural heterogeneities from stochastic variations in fluorescence resonance energy transfer distributions via photon distribution analysis. J. Phys. Chem. B 110, 6970–6978 (2006)

    CAS  PubMed  Google Scholar 

  83. Nir, E. et al. Shot-noise limited single-molecule FRET histograms: comparison between theory and experiments. J. Phys. Chem. B 110, 22103–22124 (2006)

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Kaim, G. et al. Coupled rotation within single F0F1 enzyme complexes during ATP synthesis or hydrolysis. FEBS Lett. 525, 156–163 (2002)

    CAS  PubMed  Google Scholar 

  85. Blatz, A. L. & Magleby, K. L. Correcting single channel data for missed events. Biophys. J. 49, 967–980 (1986)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank V. Orekhov at the Swedish NMR Centre for 800 MHz NMR spectrometer time, L. Kay for providing pulse programs, D. Korzhnev for sharing software for NMR relaxation data analysis and J. Hohlbein for Monte Carlo simulation software. We are grateful to K. O. Stetter for providing DNA isolated from A. aeolicus and the Advanced Biomedical Computing Center for CPU hours. This work was supported by NIH grants to D.K. and K.A.H.-W., a DOE grant to D.K., a fellowship from the American Heart Association to M.L., a Volkswagen Foundation grant to C.G.H. and M.O., and the Studienstiftung des Deutschen Volkes to M.O. The research at Harvard was supported in part by a grant from NIH to M.K.

Author Contributions K.A.H.-W., V.T., M.L. and M.O. contributed equally to this work. V.T. solved the X-ray structures with assistance from T.F., E.P., M.A.W. and G.A.P. NMR experiments were performed by K.A.H.-W., V.T. and M.W.-W., with assistance from D.K. Computation was carried out by M.L., with assistance and supervision from M.K. and D.K. FRET experiments were designed and performed by M.O. and K.A.H.-W., with assistance and supervision from C.G.H. and D.K. K.A.H.-W. and D.K. wrote the manuscript, and D.K. supervised all aspects of this work.

Author information

Author notes

  1. Magnus Wolf-Watz, Tim Fenn, Ed Pozharski, Mark A. Wilson & Christian G. Hübner

    Present address: Present addresses: University of Umeå, Department of Chemistry, SE-90187 Umeå, Sweden (M.W.-W.); Departments of Molecular and Cellular Physiology and Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA (T.F.); Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland 21201, USA (E.P.); Department of Biochemistry and the Redox Biology Center, University of Nebraska, Lincoln, Nebraska 68588, USA (M.A.W.); University at Lübeck, Institute of Physics, 23538 Lübeck, Germany (C.G.H.).,

Authors and Affiliations

  1. Department of Biochemistry and Howard Hughes Medical Institute,,

    Katherine A. Henzler-Wildman, Vu Thai, Ming Lei, Magnus Wolf-Watz & Dorothee Kern

  2. Department of Biochemistry, Brandeis University, Waltham, Massachusetts 02454, USA,

    Tim Fenn, Ed Pozharski, Mark A. Wilson & Gregory A. Petsko

  3. Institute of Physics, Martin Luther-University Halle-Wittenberg, D-06120 Halle, Germany ,

    Maria Ott & Christian G. Hübner

  4. Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA,

    Martin Karplus

  5. Laboratoire de Chimie Biophysique, ISIS, Université Louis Pasteur, F-67000 Strasbourg, France

    Martin Karplus

Authors
  1. Katherine A. Henzler-Wildman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vu Thai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ming Lei
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Maria Ott
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Magnus Wolf-Watz
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tim Fenn
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ed Pozharski
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mark A. Wilson
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Gregory A. Petsko
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Martin Karplus
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Christian G. Hübner
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Dorothee Kern
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Christian G. Hübner or Dorothee Kern.

Supplementary information

Supplementary Information

The file contains Supplementary Figures S1-S18 with Legends and Supplementary Tables S1-S4. (PDF 4067 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Henzler-Wildman, K., Thai, V., Lei, M. et al. Intrinsic motions along an enzymatic reaction trajectory. Nature 450, 838–844 (2007). https://doi.org/10.1038/nature06410

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature06410

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing