The Martell group develops catalysts that merge the benefits of enzymes and synthetic chemistry, with applications spanning sustainable synthesis, chemical biology, and plastic recycling. In one project area, we use biomolecular scaffolding to enhance the activity of abiotic catalysts under mild reaction conditions. In another project area, we use chemogenetic directed evolution platforms to enhance the activity of natural enzymes toward abiotic substrates. By merging biotechnology and synthetic chemistry, we rapidly screen millions of candidate catalysts, thus accelerating the process of catalyst discovery. We combine diverse disciplines in the creation and application of our catalysts, and we constantly encourage our group members to generate new ideas!
DNA Nanoscaffolds to Enhance Synthetic Catalysis
Synthetic catalysts drive a broader scope of chemical reactions compared to enzymes, but they lack the selectivity, activity under mild conditions, and stimuli-responsiveness of enzymes. We use nongenomic DNA to construct hybrid catalysts that accelerate reactions through pre-organization of multiple functional groups, akin to enzyme active sites but not limited to the natural amino acids and cofactors. Through DNA barcoding and combinatorial synthesis, we have developed a platform to rapidly evaluate millions of DNA nanocatalysts, and we developed switchable DNA catalysts that activate in response to specific chemical stimuli.
Synthetic Methodology
Synergistic catalysis has expanded the toolkit of eco-friendly synthetic reactions. However, synergistic catalyst systems require high co-catalyst loadings and are discovered through low-throughput methods. We combine synergistic catalysis with DNA nanostructures to enhance sustainable synthesis. We achieved >100-fold rate acceleration by holding synergistic co-catalysts in proximity on DNA scaffolds. We are applying this platform for selective transformations by attaching synergistic catalysts to DNA aptamers that bind small-molecule and biomolecular substrates. To accelerate catalyst discovery while minimizing waste, we developed a combinatorial discovery platform, in which millions of supramolecular DNA scaffolds can be screened for catalytic activity in a single test tube.
Chemical Biology
The expanding availability of bio-compatible synthetic catalysts has enabled their application in unmasking therapeutic agents, coating cells with polymers, and tagging endogenous proteins. However, synthetic catalysts are constitutively active, limiting spatial control over activity. We are using conformation-switching DNA-based catalysts to regulate the activity of abiotic reactions in response to chemical triggers. We created switchable DNA photocatalysts to control abiotic radical polymerization, and we showed that switchable DNA photocatalysts can be activated at sites of protein–protein interactions on the surface of living cells, triggering the tagging of proximal endogenous proteins for microenvironment mapping.
Representative Publications
Ogorek, A.N.; Zhou, X.; Martell, J.D. Switchable DNA Catalysts for Proximity Labeling at Sites of Protein–Protein Interactions. J. Am. Chem. Soc., 2023, 145, 16913–16923. https://pubs.acs.org/doi/full/10.1021/jacs.3c05578
Cox, C.A.; Ogorek, A.N.; Habumugisha, J.P.; Martell, J.D. Switchable DNA Photocatalysts for Radical Polymerization Controlled by Chemical Stimuli. J. Am. Chem. Soc., 2023, 145, 1818–1825. https://pubs.acs.org/doi/full/10.1021/jacs.2c11199
Merrifield, J.L.; Pimentel, E.B.; Peters-Clarke, T.M.; Nesbitt, D.J.; Coon, J.J.; Martell, J.D. DNA-Compatible Copper/TEMPO Oxidation for DNA-Encoded Libraries. Bioconjug. Chem., 2023, 34, 1380–1386. https://pubs.acs.org/doi/10.1021/acs.bioconjchem.3c00254
Kohn, E.M.; Konovalov, K.; Gomez, C.A.; Hoover, G.N.; Yik, A.K.; Huang, X.; Martell, J.D. Terminal Alkyne-Modified DNA Aptamers with Enhanced Protein Binding Affinities. ACS Chem. Biol., 2023, 18, 1976–1984. https://pubs.acs.org/doi/10.1021/acschembio.3c00183
Pimentel, E.B.; Peters-Clarke, T.M.; Coon, J.J.; Martell, J.D. DNA-Scaffolded Synergistic Catalysis. J. Am. Chem. Soc., 2021, 143, 21402–21409. https://doi.org/10.1021/jacs.1c10757
Ultrahigh-Throughput Directed Evolution of Enzymes
Enzymes exhibit remarkable activity and selectivity under mild conditions, but they often do not catalyze abiotic reactions needed for societal applications. We develop new platforms for directed evolution that merge cellular protein expression systems with chemical synthesis, enabling ultrahigh-throughput selection of enzyme mutants (from libraries of millions) with high activity toward abiotic substrates. We are applying the evolved enzymes in plastic recycling, chemical biology, and sustainable synthesis.
Plastic Recycling
Enzymes are promising catalysts for eco-friendly plastic recycling, but they require optimization through engineering or evolution for practical implementation. Existing methods to evolve plastic-degrading enzymes require low-throughput testing, representing a bottleneck in discovery of high-activity mutants. To overcome this limitation, we developed an ultrahigh-throughput platform to evolve polymer-degrading enzymes, combining yeast display with the synthesis of a probe resembling the target polymer chain. To validate the platform, we discovered mutants of polyethylene-terephthalate (PET)-degrading enzymes with enhanced activity in degrading bulk plastics. We are applying the platform to diverse enzymes, synthetic polymer chains, and reaction conditions.
Metalloenzymes for Chemical Biology and Synthesis
Heme peroxidase enzymes are versatile catalysts, generating diffusible oxygen- and nitrogen-centered radicals that can be harnessed for diverse applications, including synthesis, environmental remediation, and chemical biology. We are using high-throughput evolution together with rational protein engineering and mechanistic analysis to discover catalysts with improved activity for generating highly-reactive radicals, thus expanding the scope of substrates that can be oxidatively functionalized. We are applying these enzymes as tools to study living cells and as biocatalysts for green synthetic methodology.
Representative Publications
Fang, S.; Yin, H.; Delfosse, E. S.; Martell, J.D. Submitted.
Cribari, M.A.; Unger, M.J.; Unarta, I.C.; Ogorek, A.N.; Huang, X; Martell, J.D. Ultrahigh-Throughput Directed Evolution of Polymer-Degrading Enzymes Using Yeast Display. J. Am. Chem. Soc., 2023, 145, 27380–27389. https://pubs.acs.org/doi/10.1021/jacs.3c08291
Cribari, M.A.; Unger, M.J.; Martell, J.D. A Horseradish Peroxidase–Mediator System for Benzylic C–H Activation. ACS Catalysis, 2022, 12, 12246-12252.
https://pubs.acs.org/doi/full/10.1021/acscatal.2c03424
Porous Protein Frameworks as Catalytic Materials
Protein-based materials are promising scaffolds for creating enzyme-mimicking catalysts because they contain large nanopores that are lined with diverse functional groups. We are embedding abiotic metal complexes site-specifically within porous protein frameworks to create enzyme-mimicking active sites. This approach combines the tunable, well-defined active sites of homogeneous catalysts with the recyclability of heterogeneous catalysts. We ultimately aim to create multi-functional materials by employing protein building blocks that exhibit independent catalytic or stimuli-responsive properties.
