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Integrative, dynamic structural biology at atomic resolution—it's about time

Nature Methods volume 12, pages 307–318 (2015)Cite this article

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Abstract

Biomolecules adopt a dynamic ensemble of conformations, each with the potential to interact with binding partners or perform the chemical reactions required for a multitude of cellular functions. Recent advances in X-ray crystallography, nuclear magnetic resonance (NMR) spectroscopy and other techniques are helping us realize the dream of seeing—in atomic detail—how different parts of biomolecules shift between functional substates using concerted motions. Integrative structural biology has advanced our understanding of the formation of large macromolecular complexes and how their components interact in assemblies by leveraging data from many low-resolution methods. Here, we review the growing opportunities for integrative, dynamic structural biology at the atomic scale, contending there is increasing synergistic potential between X-ray crystallography, NMR and computer simulations to reveal a structural basis for protein conformational dynamics at high resolution.

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Figure 1: Protein dynamics across temporal (x-axis) and spatial (y-axis) scales.
Figure 2: NMR experiments report on motions across different timescales.
Figure 3: Examples of synergistic insights from NMR and X-ray crystallography.
Figure 4: At physiological temperatures, crystalline environments mildly affect biomolecular motions.
Figure 5: Cryo-cooling of protein crystals irregularly selects conformational substates.
Figure 6: In X-ray crystallography, resolution and model selection interact to affect the interpretation of conformational heterogeneity.
Figure 7: Networks of conformational exchange are evolution's engines.
Figure 8: Illustration of serial femtosecond crystallography.

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Acknowledgements

We are grateful to M. Vendruscolo and R. Ranganathan for stimulating discussions and to D.R. Hekstra and K.I. White, Green Center for Systems Biology, UT Southwestern Medical Center, for providing data for Figure 7. H.v.d.B. is supported by the US National Institute of General Medical Sciences Protein Structure Initiative (U54GM094586) at the Joint Center for Structural Genomics and by SLAC National Accelerator Laboratory LDRD (Laboratory Directed Research and Development) grant SLAC-LDRD-0014-13-2. J.S.F. is supported by US National Institutes of Health grants OD009180 and GM110580, US National Science Foundation grant STC-1231306, the Kinship Foundation Searle Scholar Program, the Pew Charitable Trusts Scholars Program and the David and Lucile Packard Foundation Fellowship.

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Authors and Affiliations

  1. Joint Center for Structural Genomics, Stanford Synchrotron Radiation Lightsource, Stanford University, Menlo Park, California, USA

    Henry van den Bedem

  2. Division of Biosciences, SLAC National Accelerator Laboratory, Stanford University, Menlo Park, California, USA

    Henry van den Bedem

  3. Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA.,

    James S Fraser

  4. California Institute for Quantitative Biology, University of California, San Francisco, San Francisco, California, USA

    James S Fraser

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Correspondence to Henry van den Bedem or James S Fraser.

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van den Bedem, H., Fraser, J. Integrative, dynamic structural biology at atomic resolution—it's about time. Nat Methods 12, 307–318 (2015). https://doi.org/10.1038/nmeth.3324

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