A Closed Form Model for Molecular Ratchet-Type Chemically Induced Dimerization Modules

• Published in: Biochemistry (Easton) 2023-01, Vol.62 (2), p.281-291
• Main Authors: Steiner, Paul J., Swift, Samuel D., Bedewitz, Matthew, Wheeldon, Ian, Cutler, Sean R., Nusinow, Dmitri A., Whitehead, Timothy A.
• Format: Article
• Language: English
• Subjects: Carrier Proteins - metabolism; Dimerization; Hormones; Ligands; Proteins - metabolism
• ISSN: 0006-2960; 1520-4995
• DOI: 10.1021/acs.biochem.2c00172

Chemical-induced dimerization (CID) modules enable users to implement ligand-controlled cellular and biochemical functions for a number of problems in basic and applied biology. A special class of CID modules occur naturally in plants and involve a hormone receptor that binds a hormone, triggering a conformational change in the receptor that enables recognition by a second binding protein. Two recent reports show that such hormone receptors can be engineered to sense dozens of structurally diverse compounds. As a closed form model for molecular ratchets would be of immense utility in forward engineering of biological systems, here we have developed a closed form model for these distinct CID modules. These modules, which we call molecular ratchets, are distinct from more common CID modules called molecular glues in that they engage in saturable binding kinetics and are characterized well by a Hill equation. A defining characteristic of molecular ratchets is that the sensitivity of the response can be tuned by increasing the molar ratio of the hormone receptor to the binding protein. Thus, the same molecular ratchet can have a pico- or micromolar EC50 depending on the concentration of the different receptor and binding proteins. Closed form models are derived for a base elementary reaction rate model, for ligand-independent complexation of the receptor and binding protein, and for homodimerization of the hormone receptor. Useful governing equations for a variety of in vitro and in vivo applications are derived, including enzyme-linked immunosorbent assay-like microplate assays, transcriptional activation in prokaryotes and eukaryotes, and ligand-induced split protein complementation.