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

  • Michael D. Daily
  • Haibo Yu
  • George N. PhillipsJr
  • Qiang CuiEmail author
Part of the Topics in Current Chemistry book series (TOPCURRCHEM, volume 337)


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.


Allostery Molecular motors Enzyme catalysis Molecular dynamics Coarse-grained models Small angle X-ray scattering Co-operativity Protein evolution 



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).


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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Michael D. Daily
    • 1
  • Haibo Yu
    • 2
  • George N. PhillipsJr
    • 3
    • 4
  • Qiang Cui
    • 5
    Email author
  1. 1.Pacific Northwest National LaboratoryRichlandUSA
  2. 2.School of ChemistryUniversity of WollongongWollongongAustralia
  3. 3.Dept. of Biochemistry and Dept. of Computer SciencesUniversity of Wisconsin-MadisonMadisonUSA
  4. 4.Dept. of Biochemistry & Cell Biology and Department of ChemistryRice UniversityHoustonUSA
  5. 5.Department of Chemistry and Theoretical Chemistry InstituteUniversity of Wisconsin MadisonMadisonUSA

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