Controlling Life with Small Molecules

The design of new protein-ligand binding interactions, particularly for complex drug-like molecules, is an unsolved problem which could enable many practical applications. My group takes on the inverse problem of traditional drug design in that we redesign existing proteins to bind known small molecule metabolites or drugs. For this lecture I will discuss two relevant examples from my group. In the first part, I discuss the challenge of designing post-translational control of enzymes. Natural systems use extensive control of enzymes post-translationally to control metabolic flux on relevant timescales of seconds. Existing literature examples of engineering similar control into proteins are scant. We redesigned T7 RNA polymerase to be activated in response to indole using a chemical recovery of structure approach first described by Matthews1. After directed evolution, these redesigned RNA polymerases have minimal activity in the absence of indole (or indole derivatives) and activate potently. We demonstrate control of gene expression exogenously, endogenously, in a co-culture, and show indole-dependent bacteriophage viability. For the second part of my talk, I will describe the redesign of a natural chemically induced dimerization system based on a plant hormone receptor2. This plant hormone receptor naturally binds to abscisic acid but can be repurposed to bind many different classes of molecules, including cannabinoids, organophosphates, nitazenes, and ergine (d-lysergic acid amide). These binders can control diverse processes in microbes and plants. I will end with the more general problem of learning molecular recognition for protein-ligands, and present a brief update on the more specific problem of antibody-antigen molecular recognition.

References

1. Eriksson, Baase, Wozniak, Matthews Nature 1992

2. Beltran, Steiner, Bedewitz,….Wheeldon, Cutler, Whitehead Nature Biotech 2022