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Studying the role of protein dynamics in an SN2 enzyme reaction using free-energy surfaces and solvent coordinates

Nature Chemistry volume 5, pages 566–571 (2013)Cite this article

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Abstract

Conformational changes are known to be able to drive an enzyme through its catalytic cycle, allowing, for example, substrate binding or product release. However, the influence of protein motions on the chemical step is a controversial issue. One proposal is that the simple equilibrium fluctuations incorporated into transition-state theory are insufficient to account for the catalytic effect of enzymes and that protein motions should be treated dynamically. Here, we propose the use of free-energy surfaces, obtained as a function of both a chemical coordinate and an environmental coordinate, as an efficient way to elucidate the role of protein structure and motions during the reaction. We show that the structure of the protein provides an adequate environment for the progress of the reaction, although a certain degree of flexibility is needed to attain the full catalytic effect. However, these motions do not introduce significant dynamical corrections to the rate constant and can be described as equilibrium fluctuations.

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Figure 1: Schematic representation of the SN2 reaction catalysed by DhlA.
Figure 2: FESs corresponding to the SN2 reaction between an acetate anion and dichloroethane.
Figure 3: The TS ensembles obtained from equilibrium and non-equilibrium pictures differ slightly, as reflected in the respective dividing surfaces.

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Acknowledgements

The authors acknowledge financial support from the Ministerio de Economía y Competitividad (MEC) through project CTQ2012-36253-C03. J.J.R-P. thanks a Juan de la Cierva contract and R.G-M. a FPU fellowship of the Ministerio de Economía y Competitividad. I.T. acknowledges helpful discussions held with D. Laage and J. T. Hynes during his sabbatical stay at the École Normale Supérieure, France. The authors acknowledge computational facilities of the Servei d'Informàtica de la Universitat de València on the ‘Tirant’ supercomputer.

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Authors and Affiliations

  1. Departament de Química Física, Universitat de València, Burjassot, 46100, Spain

    Rafael García-Meseguer & Iñaki Tuñón

  2. Departament de Química Física i Analítica,

    Sergio Martí, J. Javier Ruiz-Pernía & Vicent Moliner

  3. Universitat Jaume I, Castellón, 12071, Spain

    Sergio Martí, J. Javier Ruiz-Pernía & Vicent Moliner

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  1. Rafael García-Meseguer
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Contributions

I.T., V.M. and J.J.R‐P. designed the computational experiments. S.M. wrote the code and R.G-M. performed the calculations. I.T., V.M. and J.J.R-P. co-wrote the first version of the paper. All the authors commented and discussed the results and the final version of the manuscript.

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Correspondence to J. Javier Ruiz-Pernía or Iñaki Tuñón.

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García-Meseguer, R., Martí, S., Ruiz-Pernía, J. et al. Studying the role of protein dynamics in an SN2 enzyme reaction using free-energy surfaces and solvent coordinates. Nature Chem 5, 566–571 (2013). https://doi.org/10.1038/nchem.1660

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