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Dynamics in Enzyme Catalysis pp 139–164Cite as

Allosteric Activation Transitions in Enzymes and Biomolecular Motors: Insights from Atomistic and Coarse-Grained Simulations

Part of the Topics in Current Chemistry book series (TOPCURRCHEM,volume 337)

Abstract

The chemical step in enzymes is usually preceded by a kinetically distinct activation step that involves large-scale conformational transitions. In “simple” enzymes this step corresponds to the closure of the active site; in more complex enzymes, such as biomolecular motors, the activation step is more complex and may involve interactions with other biomolecules. These activation transitions are essential to the function of enzymes and perturbations in the scale and/or rate of these transitions are implicated in various serious human diseases; incorporating key flexibilities into engineered enzymes is also considered a major remaining challenge in rational enzyme design. Therefore it is important to understand the underlying mechanism of these transitions. This is a significant challenge to both experimental and computational studies because of the allosteric and multi-scale nature of such transitions. Using our recent studies of two enzyme systems, myosin and adenylate kinase (AK), we discuss how atomistic and coarse-grained simulations can be used to provide insights into the mechanism of activation transitions in realistic systems. Collectively, the results suggest that although many allosteric transitions can be viewed as domain displacements mediated by flexible hinges, there are additional complexities and various deviations. For example, although our studies do not find any evidence for “cracking” in AK, our results do underline the contribution of intra-domain properties (e.g., dihedral flexibility) to the rate of the transition. The study of mechanochemical coupling in myosin highlights that local changes important to chemistry require stabilization from more extensive structural changes; in this sense, more global structural transitions are needed to activate the chemistry in the active site. These discussions further emphasize the importance of better understanding factors that control the degree of co-operativity for allosteric transitions, again hinting at the intimate connection between protein stability and functional flexibility. Finally, a number of topics of considerable future interest are briefly discussed.

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Acknowledgments

We thank all other collaborators who have also made significant contributions to the studies discussed here. The research has been generously supported by NIH (R01GM071428, R01GM084028 and NLM training grant 5T15LM007359).

Author information

Authors and Affiliations

  1. Pacific Northwest National Laboratory, Richland, Washington, 99352, USA

    Michael D. Daily

  2. School of Chemistry, University of Wollongong, Wollongong, NSW, 2522, Australia

    Haibo Yu

  3. Dept. of Biochemistry and Dept. of Computer Sciences, University of Wisconsin-Madison, Madison, WI, 53706, USA

    George N. Phillips Jr

  4. Dept. of Biochemistry & Cell Biology and Department of Chemistry, Rice University, Houston, TX, 77006, USA

    George N. Phillips Jr

  5. Department of Chemistry and Theoretical Chemistry Institute, University of Wisconsin Madison, 1101 University Ave., Madison, WI, 53706, USA

    Qiang Cui

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  1. Michael D. Daily
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Correspondence to Qiang Cui .

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Editors and Affiliations

  1. Department of Chemistry Department of Molecular and Cell Biology, University of California The california institute for Quantitativ, Berkeley, CA, USA

    Judith Klinman

  2. Department of Chemistry, University of Illinois at Urbana-Champai, Urbana, Illinois, USA

    Sharon Hammes- Schiffer

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Daily, M.D., Yu, H., Phillips, G.N., Cui, Q. (2013). Allosteric Activation Transitions in Enzymes and Biomolecular Motors: Insights from Atomistic and Coarse-Grained Simulations. In: Klinman, J., Hammes- Schiffer, S. (eds) Dynamics in Enzyme Catalysis. Topics in Current Chemistry, vol 337. Springer, Berlin, Heidelberg. https://doi.org/10.1007/128_2012_409

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