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The role of dynamic conformational ensembles in biomolecular recognition

Nature Chemical Biology volume 5, pages 789–796 (2009)Cite this article

An Erratum to this article was published on 01 December 2009

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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.

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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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Authors and Affiliations

  1. Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania, USA

    David D Boehr

  2. Basic Science Program, SAIC-Frederick, Inc., Center for Cancer Research Nanobiology Program, National Cancer Institute-Frederick, Frederick, Maryland, USA

    Ruth Nussinov

  3. Department of Human Genetics, Sackler Institute of Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

    Ruth Nussinov

  4. Department of Molecular Biology and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA

    Peter E Wright

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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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