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The Importance of the Scaffold for de Novo Enzymes: A Case Study with Kemp Eliminase

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    The Importance of the Scaffold for de Novo Enzymes: A Case Study with Kemp Eliminase
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    † ‡ § †Department of Chemical and Biomolecular Engineering, ‡Department of Chemistry, and §Department of Bioengineering, University of California, Berkeley, Berkeley, California 94720, United States
    ∥ Chemical Sciences Division, Lawrence Berkeley National Laboratories, Berkeley, California 94720, United States
    *[email protected]
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    Journal of the American Chemical Society

    Cite this: J. Am. Chem. Soc. 2017, 139, 16, 5793–5800
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    https://doi.org/10.1021/jacs.6b12265
    Published April 6, 2017
    Copyright © 2017 American Chemical Society
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    Abstract

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    We report electric field values relevant to the reactant and transition states of designed Kemp eliminases KE07 and KE70 and their improved variants from laboratory directed evolution (LDE), using atomistic simulations with the AMOEBA polarizable force field. We find that the catalytic base residue contributes the most to the electric field stabilization of the transition state of the LDE variants of the KE07 and KE70 enzymes, whereas the electric fields of the remainder of the enzyme and solvent disfavor the catalytic reaction in both cases. By contrast, we show that the electrostatic environment plays a large and stabilizing role for the naturally occurring enzyme ketosteroid isomerase (KSI). These results suggest that LDE is ultimately a limited strategy for improving de novo enzymes since it is largely restricted to optimization of chemical positioning in the active site, thus yielding a ∼3 order magnitude improvement over the uncatalyzed reaction, which we suggest may be an absolute upper bound estimate based on LDE applied to comparable de novo Kemp eliminases and other enzymes like KSI. Instead de novo enzymatic reactions could more productively benefit from optimization of the electrostatics of the protein scaffold in early stages of the computational design, utilizing electric field optimization as guidance.

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    • Parameterization, dipole moment and active site residue details. Tables for sequence of KE07/KE70, dipole moments, preorganization/reorganization energy breakup, field values for specific residues, scaffold, and solvent at the three bonds (PDF)

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    This article is cited by 56 publications.

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    Cite this: J. Am. Chem. Soc. 2017, 139, 16, 5793–5800
    Click to copy citationCitation copied!
    https://doi.org/10.1021/jacs.6b12265
    Published April 6, 2017
    Copyright © 2017 American Chemical Society
    Request reuse permissions

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