Lippard's research activities are at the interface of biology and inorganic chemistry. Lippard focuses on understanding the physical and structural properties of metal complexes, their synthesis and reactions, and the involvement of metal ions in biological systems. The formation and breaking of molecular bonds underlie many biochemical transformations. Purely inorganic substances such as iron are often required in essential organic reactions, e.g. oxygen binding in the hemoglobin family. Lippard attempts to better understand the role of metal complexes in the physiology and pathology of existing biological systems, and to identify possible applications of metal ions in medical treatment. He has made major contributions in a number of areas, including the development of
platinum-based anticancer drugs such as the
cisplatin family. Another area of interest is the structure and function of
methane and
enzymes that consume greenhouse gas hydrocarbons. In metalloneurochemistry, he studies the molecular activity of metal ions in the brain and develops optical and MRI sensors for binding, tracking, and measuring metal ions as they interact with neurotransmitters and other biological signaling agents. Early work in Lippard's lab on the interaction of
metal complexes with
nucleic acids led to the discovery of the first
metallo-intercalators and eventually to the understanding of the mechanisms of cisplatin. Lippard and his students examined sequences of DNA and RNA and incorporated sulfur atoms into the sugar-phosphate backbone, where they selectively bound mercury or platinum complexes to specific positions. Karen Jennette's discovery that sterically encumbered platinum complexes were more successful in binding to sulfur atoms in tRNA than mercury salts led researchers to propose that the platinum complexes intercalated between the double-stranded RNA's base pairs. Using fiber X-ray diffraction, Peter Bond and others were able to display the intercalated platinum complex and to confirm predictions that the spacing of intercalators in DNA base pairs would follow the neighbor exclusion rule. This established the groundwork for subsequent work on intercalative binding. Further experiments have explored the mechanisms through which platinum drugs bind their biological targets and led to insights into their anticancer activity. Important results include the identification of an intrastrand d(pGpG) cross-link as the major adduct on platinated single-stranded DNA, identification of the major adduct on double-stranded DNA, the binding of high-mobility-group proteins to platinated DNA cross-links. Using X-ray crystallography and other techniques, Lippard and his coworkers have examined the mechanisms involved in binding cisplatin to DNA fragments, to better understand how cisplatin invades tumor cells and interferes with their activity. As well as the intrastrand cross links created by cisplatin, monofunctional metal complexes may suggest possible cancer treatments. A related line of research in Lippard's laboratory involves platinum blues. Jacqueline Barton was the first person to synthesize and structurally characterize a crystalline platinum blue, pyridone blue. Since then, extensive research has been done on the structure, properties, and reactions of such complexes.
Methane monooxygenases Members of the Lippard laboratory studying macromolecular crystallography have explored the structure, mechanisms and activity of bacterial multicomponent monooxygenases. Methane monooxygenases are enzymes that occur in bacteria called methanotrophs. The primary function of this enzyme is the
hydroxylation of methane to methanol as the first step in
methane metabolism.
Amy Rosenzweig determined the protein x-ray structure of the soluble form of
methane monooxygenase (MMO) as Lippard's graduate student. Lippard has used X-ray diffraction and a variety of other methods to study such compounds, greatly expanding our understanding of their structure and function. MMO is vital to Earth's carbon cycle, and knowledge of its structure may help to develop clean technologies for methanol-based fuels.
Iron complexes Lippard and his students have also studied the synthesis of diiron complexes such as diiron hydroxylase to better understand the activities of metal atoms in biological molecules. They have developed model compounds for carboxylate-bridged diiron metalloenzymes which can be compared with corresponding biological forms. They have synthesized analogues of the diiron carboxylate cores of MMO and related carboxylate-bridged diiron proteins such as the dioxygen transporter
hemerythrin. In 2010, Lippard received the Ronald Breslow Award for his work on nonheme iron proteins. Also exciting was the synthesis of a "molecular ferric wheel" by Kingsley Taft, the first wheel structure to be observed in self-assembled polymetallic chemistry. A nearly perfect circle containing ten ferric ions, the structure spontaneously assembled in methanolic solutions of diiron(III) oxo complexes, which were being studied to better understand polyiron oxo protein cores like those of hemerythrin. Although no particular use is known for the ferric wheel, it and subsequent ring-shaped homometallic molecular clusters are of interest as a subclass of molecular magnets. Another novel complex was a "ferric triple-decker", containing three parallel triangular iron units and a triple bridge of six citrate ligands.
Metalloneurochemistry Lippard is considered a founder of
metalloneurochemistry, Working at the interface of inorganic chemistry and neuroscience, he has devised fluorescent imaging agents for studying mobile zinc and nitric oxide and their effects on neurotransmission and other forms of biological signaling. ==Companies==