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Computational remodeling of an enzyme conformational landscape for altered substrate selectivity

Author

Listed:
  • Antony D. St-Jacques

    (University of Ottawa
    University of Ottawa)

  • Joshua M. Rodriguez

    (University of California, Merced)

  • Matthew G. Eason

    (University of Ottawa
    University of Ottawa)

  • Scott M. Foster

    (University of Ottawa
    University of Ottawa)

  • Safwat T. Khan

    (University of Ottawa
    University of Ottawa)

  • Adam M. Damry

    (University of Ottawa
    University of Ottawa)

  • Natalie K. Goto

    (University of Ottawa
    University of Ottawa)

  • Michael C. Thompson

    (University of California, Merced)

  • Roberto A. Chica

    (University of Ottawa
    University of Ottawa)

Abstract

Structural plasticity of enzymes dictates their function. Yet, our ability to rationally remodel enzyme conformational landscapes to tailor catalytic properties remains limited. Here, we report a computational procedure for tuning conformational landscapes that is based on multistate design of hinge-mediated domain motions. Using this method, we redesign the conformational landscape of a natural aminotransferase to preferentially stabilize a less populated but reactive conformation and thereby increase catalytic efficiency with a non-native substrate, resulting in altered substrate selectivity. Steady-state kinetics of designed variants reveals activity increases with the non-native substrate of approximately 100-fold and selectivity switches of up to 1900-fold. Structural analyses by room-temperature X-ray crystallography and multitemperature nuclear magnetic resonance spectroscopy confirm that conformational equilibria favor the target conformation. Our computational approach opens the door to targeted alterations of conformational states and equilibria, which should facilitate the design of biocatalysts with customized activity and selectivity.

Suggested Citation

  • Antony D. St-Jacques & Joshua M. Rodriguez & Matthew G. Eason & Scott M. Foster & Safwat T. Khan & Adam M. Damry & Natalie K. Goto & Michael C. Thompson & Roberto A. Chica, 2023. "Computational remodeling of an enzyme conformational landscape for altered substrate selectivity," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41762-0
    DOI: 10.1038/s41467-023-41762-0
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    References listed on IDEAS

    as
    1. Joe A. Kaczmarski & Mithun C. Mahawaththa & Akiva Feintuch & Ben E. Clifton & Luke A. Adams & Daniella Goldfarb & Gottfried Otting & Colin J. Jackson, 2020. "Altered conformational sampling along an evolutionary trajectory changes the catalytic activity of an enzyme," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    2. Katherine Henzler-Wildman & Dorothee Kern, 2007. "Dynamic personalities of proteins," Nature, Nature, vol. 450(7172), pages 964-972, December.
    3. James S. Fraser & Michael W. Clarkson & Sheena C. Degnan & Renske Erion & Dorothee Kern & Tom Alber, 2009. "Hidden alternative structures of proline isomerase essential for catalysis," Nature, Nature, vol. 462(7273), pages 669-673, December.
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