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Predicting Catalytic Proton Donors and Nucleophiles in Enzymes: How Adding Dynamics Helps Elucidate the Structure–Function Relationships

  • Yandong Huang
    Yandong Huang
    Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland 21201, United States
    More by Yandong Huang
  • , 
  • Zhi Yue
    Zhi Yue
    Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland 21201, United States
    More by Zhi Yue
    Orcidhttp://orcid.org/0000-0002-4231-7474
  • , 
  • Cheng-Chieh Tsai
    Cheng-Chieh Tsai
    Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland 21201, United States
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  • , 
  • Jack A. Henderson
    Jack A. Henderson
    Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland 21201, United States
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  • , and 
  • Jana Shen*
    Jana Shen
    Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland 21201, United States
    *E-mail: [email protected]
    More by Jana Shen
    Orcidhttp://orcid.org/0000-0002-3234-0769
Cite this: J. Phys. Chem. Lett. 2018, 9, 6, 1179–1184
Publication Date (Web):February 20, 2018
https://doi.org/10.1021/acs.jpclett.8b00238
Copyright © 2018 American Chemical Society
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    Abstract

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    Despite the relevance of understanding structure–function relationships, robust prediction of proton donors and nucleophiles in enzyme active sites remains challenging. Here we tested three types of state-of-the-art computational methods to calculate the pKa’s of the buried and hydrogen bonded catalytic dyads in five enzymes. We asked the question what determines the pKa order, i.e., what makes a residue proton donor vs a nucleophile. The continuous constant pH molecular dynamics simulations captured the experimental pKa orders and revealed that the negative nucleophile is stabilized by increased hydrogen bonding and solvent exposure as compared to the proton donor. Surprisingly, this simple trend is not apparent from crystal structures and the static structure-based calculations. While the generality of the findings awaits further testing via a larger set of data, they underscore the role of dynamics in bridging enzyme structures and functions.

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jpclett.8b00238.

    • Detailed computational protocols and supplementary figures showing time series plots, pKa plots, plots of the number of H bonds, occupancy of the H bonds, fraction of deprotonation, fractional solvent accessible surface area, and hydration number results (PDF)

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