Research

The Bhagi-Damodaran lab uses tools in chemistry and biology to discover new drugs and design novel catalysts. To achieve these goals, we focus on proteins that use metals as cofactors, called metalloproteins. Metalloproteins are excellent candidates for drug discovery and catalysis as both biochemical (e.g. crystallography, activity assays, NMR) and inorganic chemistry (e.g. UV-Vis, EPR, EXAFS) techniques can be used to investigate and characterize them. Research in the Bhagi-Damodaran lab is focused on (1) Blocking and rewiring metalloprotein-based redox signaling towards next-generation therapeutics and (2) Engineering new catalysts via rational design and directed evolution of metal-dependent proteins and enzymes.

We focus on the development and application of new electronic structure theories. Specifically, we are interested in multi-scale models, which allow for the study of large and extended systems. We are developing quantum-embedding theories, which treat different regions of the system at different levels of accuracy. This allows for a high chemical accuracy in a small region, such as an active site of a catalyst, and a less accurate, but more computationally efficient description of the remainder. These tools can then be used to perform first-principle studies on large, reactive, and condensed phase systems. We are interested in applying these methods to metalloenzymes, heterogeneous catalysts, and metal-organic frameworks.

We study the mechanisms used by metalloenzymes to activate molecular oxygen. The specific enzymes we study fall into two broad classes. Some catalyze incorporation one or both atoms of oxygen from dioxygen into their organic substrates (methane monooxygenase, aromatic ring cleaving dioxygenases, or cis-diol forming Rieske dioxygenases).  The second class create an in situ reagent from the activate oxygen for biosynthetic purposes without oxygen incorporation (isopenicillin N synthase, fosfomycin synthase, ACC oxidase). We utilize a variety of techniques including EPR spectroscopy, transient kinetics, crystallography, and diagnostic substrate reactions. One of our main goals is to discover the intermediates in the chemical reaction cycle of oxygen activating enzymes. These efforts have led to the discovery of intermediates in each of the enzyme classes listed above, most recently culminating in the solution of the crystal structures of the key intermediates in the extradiol aromatic ring cleaving dioxygenase class.

We seek to unravel how metalloenzymes convert small molecules using inorganic chemistry. Our approach is to develop, investigate, and exploit unusual structure-function motifs that are found in nature. For example, Ni-Fe carbon monoxide dehydrogenase may utilize metal-metal bonding for activating carbon dioxide. By preparing model coordination complexes featuring reactive metal-metal bonds, we can extract a detailed picture of their physical and electronic structures that may elucidate the underpinnings of their function. We can then apply this understanding towards new systems that improve on the natural counterparts in activity, selectivity, and substrate scope.

Our group employs coordination and supramolecular chemistry to solve medical and environmental problems. We exploit siderophores, natural products synthesized by bacteria to chelate iron, as new diagnostic and theranostic tools for bacterial infections. We design and synthesize analogues of these natural products that can rapidly detect, quantify and identify bacteria in complex media. We design unique metal-based receptors to modernize dialysis and treat hyperphosphatemia - a condition affecting millions of patients with kidney diseases. As part of our environmental efforts, we are designing new complexes, supramolecular receptors and polymeric membranes that can catch pollutants from lakes and rivers. Our current goal is to design new tools that can economically remove phosphates and nitrates from surface water contaminated with agricultural run-offs.

The Que group focuses on bio-inorganic chemistry, specifically on the topic of iron, oxygen and biocatalysis. Our research efforts, involving a combination of biochemical, synthetic inorganic, and spectroscopic approaches, are aimed at understanding the oxygen activation mechanisms of nonheme iron enzymes, designing functional models for such enzymes, trapping and characterizing reaction intermediates, and developing bio-inspired oxidation catalysts for green chemistry applications. Targets include methane monooxygenase and related diiron enzymes, as well as monoiron enzymes with a common 2-His-1-carboxylate facial triad active site, including enzymes that require alpha-keto acids as co-substrates, Rieske dioxygenases that carry out cis-dihydroxylation of arene double bonds, and a novel pair of Fe- and Mn-dependent catechol dioxygenases. Intermediates of prime interest are high-valent oxoiron species thought to be carry out the most challenging oxidative transformations. The picture shows the crystal structure of an oxoiron(IV) complex we have characterized, such as the hydroxylation of methane and the conversion of water to O₂.

In the Wilmot lab we seek to understand the structural basis of catalysis by metalloenzymes. The principle tool of our research is macromolecular X-ray crystallography, in combination with spectroscopic techniques both in the crystal and solution, kinetics, mass spectrometry and mutagenesis. We freeze trap catalytic intermediates in the crystal, which give structural "snapshots" along the reaction pathway. These are then assembled into a "movie of catalysis" at the molecular level. We work on MauG (a di-heme enzyme that is involved in the synthesis of the protein-derived cofactor, tryptophan tryptophylquinone [TTQ]); chlorite dismutase (a key enzyme in bacteria mediated chlorite breakdown in water treatment facilities); nickel homeostasis in bacteria (a potential drug target).