Lab makes 3-D enzyme mimicking architectures using full pallet of synthetic chemistry

By Aadhishre Kasat
Department Communications & Student Researcher (Buller)

The Martell group’s research focuses on making artificial enzymes and artificial receptors by combining biomolecules with synthetic molecules.

“We synthetically modify individual DNA arms by using functional groups that are not found in naturally occur- ring amino acids and cofactors, therefore broadening the scope of our reactivity,” said Prof. Jeffrey Martell. “We then rely on complementary base-pairing for the arms to self-assemble into a 3-D cage, such that the attached functional groups are displayed into a central cavity.”

Martell’s approach of creating artificial enzymes using DNA scaffolds is sophisticated. Based on collision theory, for a successful reaction to occur, the reactants colliding must possess a minimum energy and be oriented in a manner favorable for the reaction to occur. The movement of the catalysts and reagents in a typical synthetic chemistry reaction is largely administered by diffusion. While we can tweak factors such as heat and concentration to increase the total number of collisions, there will still be many collisions that will not result in a successful reaction.

According to Martell, enzymes are one step forward. Enzymes are 3-D structures where the catalytic activity is sequestered in the internal cavity of the structure, where the functional groups are already arranged in a conformation most favorable for reaction to occur. Since enzymes are closed structures, the substrate can enter only in a specific manner such that it is oriented perfectly for the reaction to occur. This isn’t to say that diffusion doesn’t occur in biological systems; it does. This just means that reactions occur more efficiently in enzymes because of their specific 3-D structure, yielding much faster reaction rates.

By making 3-D enzyme mimicking architectures using the full palette of synthetic chemistry, the Martell lab is exploiting not just the expanded reactivity offered by synthetic chemistry but also the specificity offered by enzymatic structures, resulting in reactions with incredibly high rates.

The strength and the challenge of the project are the same — the 3-D enzyme mimicking structure.

“While this structure offers benefits of biocatalysis, even the smallest of changes in conformation can drastically affect activity,” Martell said. “It is really challenging to ensure that the DNA scaffold folds in a manner such that the synthetic molecules are organized in the most favorable manner.”

Prof. Jeffrey Martell and Edward Pimentel headshots

Even with challenges, the Martell lab has had success. A recently submitted paper spearheaded by fourth-year graduate student Edward Pimentel showed that DNA scaffolds can be used to accelerate chemical reactions.

“Edward attached two co-catalysts on the same side of the DNA helix to perform an alcohol oxidation reaction and showed that when DNA is used as a scaffold, the reaction occurs much faster than when it isn’t,” explained Martell.

As seen in the figure, Pimentel completely switched the reaction off by altering the conformation of the DNA scaffold. This is very interesting because of its applications in sensing and targeted therapeutics.

Graduate researcher Edward Pimentel showed that changing the conformation of the DNA scaffold, thereby increasing the distance between the co-catalysts, and inhibiting their interaction, resulted in the reaction completely shutting off.