I am a member of the Protein Engineering and Chemistry Group within the Laboratory of Chemical Physics. We apply kinetics, thermodynamics, and other biochemical and physicochemical approaches to elucidate enzymatic reaction mechanisms and protein-protein and protein-small molecule interactions. We carry out ongoing studies on retroviral proteases (PR). Specific interests include the mechanism and inhibition of retroviral PR maturation from its Gag-Pol polyprotein precursor. Our findings may help to identify inhibitors that target the folding or transient dimerization of the PR precursor and to provide novel approaches to overcoming drug resistance.
Prior to 2007, my research in the Section on Oxidation Mechanisms of the Laboratory of Bioorganic Chemistry focused on the organic chemistry and biochemistry of diol epoxides resulting from mammalian oxidative metabolism of carcinogenic polycyclic aromatic hydrocarbons (PAHs). PAHs are widespread environmental pollutants. Diol epoxides react with purine bases in DNA to form covalent adducts. This results in erroneous DNA replication, a potential mechanism for initiation of cancer. Our primary interests were in the reactivity and reaction mechanisms of the PAH diol epoxides. We also studied the synthesis, purification, and spectroscopic characterization of modified oligonucleotides containing specific PAH adducts. These studies were carried out in collaboration with biochemists, nuclear magnetic resonance spectroscopists, and crystallographers. Our research examined the effects of these adducts on the replication of DNA by polymerases and on DNA processing by other enzymes, such as helicases and topoisomerases.