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Solvent Entropy Contributions to Catalytic Activity in Designed and Optimized Kemp Eliminases

  • Saurabh Belsare
    Saurabh Belsare
    The UC Berkeley-UCSF Graduate Program in Bioengineering, Lawrence Berkeley National Laboratories, Berkeley, California 94720, United States
  • Viren Pattni
    Viren Pattni
    Max-Planck-Institut fur Kohlenforschung, 45470 Mülheim an der Ruhr, Germany
    More by Viren Pattni
  • Matthias Heyden*
    Matthias Heyden
    Max-Planck-Institut fur Kohlenforschung, 45470 Mülheim an der Ruhr, Germany
    *[email protected]
  • , and 
  • Teresa Head-Gordon*
    Teresa Head-Gordon
    The UC Berkeley-UCSF Graduate Program in Bioengineering,  Kenneth S. Pitzer Center for Theoretical Chemistry,  Department of Chemistry,  Department of Bioengineering,  Department of Chemical and Biomolecular Engineering, University of California  and  Chemical Sciences Division, Lawrence Berkeley National Laboratories, Berkeley, California 94720, United States
    *[email protected]
Cite this: J. Phys. Chem. B 2018, 122, 21, 5300–5307
Publication Date (Web):September 12, 2017
https://doi.org/10.1021/acs.jpcb.7b07526
Copyright © 2017 American Chemical Society

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    Abstract

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    We analyze the role of solvation for enzymatic catalysis in two distinct, artificially designed Kemp Eliminases, KE07 and KE70, and mutated variants that were optimized by laboratory directed evolution. Using a spatially resolved analysis of hydration patterns, intermolecular vibrations, and local solvent entropies, we identify distinct classes of hydration water and follow their changes upon substrate binding and transition state formation for the designed KE07 and KE70 enzymes and their evolved variants. We observe that differences in hydration of the enzymatic systems are concentrated in the active site and undergo significant changes during substrate recruitment. For KE07, directed evolution reduces variations in the hydration of the polar catalytic center upon substrate binding, preserving strong protein–water interactions, while the evolved enzyme variant of KE70 features a more hydrophobic reaction center for which the expulsion of low-entropy water molecules upon substrate binding is substantially enhanced. While our analysis indicates a system-dependent role of solvation for the substrate binding process, we identify more subtle changes in solvation for the transition state formation, which are less affected by directed evolution.

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jpcb.7b07526.

    • KE70 mutations, ligand dipole moment for EL vs EL*, and changes in residue nature due to mutations (PDF)

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    Cited By

    This article is cited by 12 publications.

    1. Saumyak Mukherjee, Lars V. Schäfer. Spatially Resolved Hydration Thermodynamics in Biomolecular Systems. The Journal of Physical Chemistry B 2022, 126 (20) , 3619-3631. https://doi.org/10.1021/acs.jpcb.2c01088
    2. Tawny N. Fajardo, Matthias Heyden. Dissecting the Conformational Free Energy of a Small Peptide in Solution. The Journal of Physical Chemistry B 2021, 125 (18) , 4634-4644. https://doi.org/10.1021/acs.jpcb.1c00699
    3. James W. Harris, Jason S. Bates, Brandon C. Bukowski, Jeffrey Greeley, Rajamani Gounder. Opportunities in Catalysis over Metal-Zeotypes Enabled by Descriptions of Active Centers Beyond Their Binding Site. ACS Catalysis 2020, 10 (16) , 9476-9495. https://doi.org/10.1021/acscatal.0c02102
    4. Valerie Vaissier Welborn, Teresa Head-Gordon. Computational Design of Synthetic Enzymes. Chemical Reviews 2019, 119 (11) , 6613-6630. https://doi.org/10.1021/acs.chemrev.8b00399
    5. Wook Shin, Zhongyue J. Yang. Computational Strategies for Entropy Modeling in Chemical Processes. Chemistry – An Asian Journal 2023, 18 (9) https://doi.org/10.1002/asia.202300117
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    8. H. Adrian Bunzel, J.L. Ross Anderson, Adrian J. Mulholland. Designing better enzymes: Insights from directed evolution. Current Opinion in Structural Biology 2021, 67 , 212-218. https://doi.org/10.1016/j.sbi.2020.12.015
    9. Laurens D. M. Peters, Johannes C. B. Dietschreit, Jörg Kussmann, Christian Ochsenfeld. Calculating free energies from the vibrational density of states function: Validation and critical assessment. The Journal of Chemical Physics 2019, 150 (19) https://doi.org/10.1063/1.5079643
    10. Matthias Heyden. Disassembling solvation free energies into local contributions—Toward a microscopic understanding of solvation processes. WIREs Computational Molecular Science 2019, 9 (2) https://doi.org/10.1002/wcms.1390
    11. Yashraj Kulkarni, Shina Caroline Lynn Kamerlin. Computational physical organic chemistry using the empirical valence bond approach. 2019, 69-104. https://doi.org/10.1016/bs.apoc.2019.07.001
    12. Anna Krylov, Theresa L. Windus, Taylor Barnes, Eliseo Marin-Rimoldi, Jessica A. Nash, Benjamin Pritchard, Daniel G. A. Smith, Doaa Altarawy, Paul Saxe, Cecilia Clementi, T. Daniel Crawford, Robert J. Harrison, Shantenu Jha, Vijay S. Pande, Teresa Head-Gordon. Perspective: Computational chemistry software and its advancement as illustrated through three grand challenge cases for molecular science. The Journal of Chemical Physics 2018, 149 (18) https://doi.org/10.1063/1.5052551

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