Zinc Fingers as Templates for Metal Complex Interactions

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DNA is recognized with exquisite specificity by a group of proteins collectively known as zinc fingers. The DNA-zinc finger interaction has important biological consequences, for example when cells divide or viruses multiply. The proposed experiments will explore a newly discovered means for disrupting the interaction using metal containing compounds (specifically platinum) discovered in the laboratory of the principal investigator. Future research will be conducted to understand and control this property for the development of new medicines like anti-viral (especially HIV) compounds. The approach will be both experimental (chemical and biological) and theoretical (computational). The project represents an excellent example of the linkage between basic research and discovery on one hand, and important societal benefits on the other. The research project will also be part of an international collaboration exposing graduate students to the subject, and to cross-cultural experiences.With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Nicholas Farrell from Virginia Commonwealth University to characterize reactions of zinc finger proteins by the systematic study of steric and electronic effects of functionalized coordination compounds on the kinetics and thermodynamics of zinc displacement and disruption of protein structure and function. A specific focus will be on the HIV NCp7 nucleocapsid protein (NC), and the mechanism of platinum-metal nucleobases as nucleocapsid-nucleic acid antagonists through interruption of the NC-RNA(DNA) interaction will be examined. The factors affecting selective "non-covalent" ligand-biomolecule recognition through enhanced pi-pi; stacking between metallated nucleobases and the tryptophan-containing nucleocapsid will be examined. Secondly, such recognition can lead to formation of the "covalent" metal-thiolate bond and subsequent zinc ejection. We will explore the analogy of weak "organic" and "inorganic" electrophiles to design specific interactions differentiating the distinct Cys2His2, Cys3His and Cys4 zinc finger-binding sites.