Research

Our group combines experimental and computational methods to understand mechanisms of reactions important for chemistry and biology. Specifically, we utilize traditionally physical methods, primarily mass spectrometry and computational chemistry, to tackle problems at the chemistry/biology interface, focusing on catalysis. We work on both biological catalysis, uncovering the mechanisms by which enzymes excise damaged DNA from the genome; as well as organic catalysis, examining N-heterocyclic carbenes as organocatalysts.

 

Organic catalysis. N-Heterocyclic carbenes (NHCs) are organic species that have a wide variety of applications, including as effective ligands for transition-metal-catalyzed reactions; as catalysts in their own right, for a range of organic transformations; and in protonated form, as environmentally “clean” (green) nonvolatile solvents for organic reactions (ionic liquids). Despite the widespread use of NHCs, their fundamental reactivity is not fully characterized. Our group has developed novel mass spectrometric methodology to measure the thermochemical properties and explore the reactivity of such carbenes. Recent work has provided the first experimental evidence for the high nucleophilicity of a series of diamidocarbenes, which are newly designed NHCs that display both nucleophilic and electrophilic properties (in collaboration with Professor Christopher Bielawski, UT Austin). We are also working on elucidating the mechanism of the Stetter reaction, a highly useful synthetic transformation catalyzed by NHCs. This work will contribute to the design and understanding of new carbene scaffolds and the development of new catalysts for organic transformations

 

Biological catalysis. DNA reactivity and stability are critical issues for all living beings. The heterocyclic bases of nucleic acids are targets for toxins that damage DNA, events that are linked to carcinogenesis and cell death. A family of enzymes called DNA glycosylases protect the human genome from the lethal effects of mutated DNA by the base excision repair pathway. We have developed a hypothesis to explain how certain glycosylases differentiate normal from damaged bases. Various lines of evidence have led to the conclusion that glycosylases achieve selectivity by providing a hydrophobic environment that helps differentiate normal from damaged DNA bases. The gas phase is the “ultimate” hydrophobic environment, and our studies of reactions by calculations and novel mass spectrometry methods reveal intrinsic reactivity that is relevant to biological hydrophobic environments such as enzyme active sites. The group is also embarking on enzyme kinetics studies to test hypotheses regarding glycosylase mechanisms. Given the cytotoxic and mutagenic effects of DNA damage, this work has broad implications for aging and for diseases including cancer.