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Combinatorial Control through Allostery

  • Vahe Galstyan
    Vahe Galstyan
    Biochemistry and Molecular Biophysics Option, California Institute of Technology, Pasadena, California 91125, United States
  • Luke Funk
    Luke Funk
    Harvard-MIT Division of Health Sciences and Technology and the Broad Institute of MIT and Harvard, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
    More by Luke Funk
  • Tal Einav
    Tal Einav
    Department of Physics, California Institute of Technology, Pasadena, California 91125, United States
    More by Tal Einav
  • , and 
  • Rob Phillips*
    Rob Phillips
    Department of Physics,  Department of Applied Physics  and  Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125, United States
    *E-mail: [email protected]. Phone: (626) 395-3374.
    More by Rob Phillips
Cite this: J. Phys. Chem. B 2019, 123, 13, 2792–2800
Publication Date (Web):February 15, 2019
https://doi.org/10.1021/acs.jpcb.8b12517
Copyright © 2019 American Chemical Society

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    Abstract

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    Many instances of cellular signaling and transcriptional regulation involve switch-like molecular responses to the presence or absence of input ligands. To understand how these responses come about and how they can be harnessed, we develop a statistical mechanical model to characterize the types of Boolean logic that can arise from allosteric molecules following the Monod–Wyman–Changeux (MWC) model. Building upon previous work, we show how an allosteric molecule regulated by two inputs can elicit AND, OR, NAND, and NOR responses but is unable to realize XOR or XNOR gates. Next, we demonstrate the ability of an MWC molecule to perform ratiometric sensing—a response behavior where activity depends monotonically on the ratio of ligand concentrations. We then extend our analysis to more general schemes of combinatorial control involving either additional binding sites for the two ligands or an additional third ligand and show how these additions can cause a switch in the logic behavior of the molecule. Overall, our results demonstrate the wide variety of control schemes that biological systems can implement using simple mechanisms.

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jpcb.8b12517.

    • Details on aforementioned derivations and calculations (PDF)

    • Supporting Mathematica notebook from which all protein activity response plots and gate quality metric plots can be reproduced (ZIP)

    • Supporting Jupyter Notebooks, where the set of functionally unique gates and constraints conditions are derived (ZIP)

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    Cited By

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