Platinum Metal Complexes as DNA-Protein Cross-linking Agents

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Dr. Nicolas P. Farrell, Chemistry Department, Virginia Commonwealth University, is supported by the Inorganic, Bioinorganic, and Organometallic Chemistry Program of the Chemistry Division to explore the fundamental chemistry of DNA-protein interactions involving platinated (or metallated) nucleobases and oligonucleotides with zinc finger proteins. The factors affecting selective recognition, ternary Pt-DNA-protein adduct formation, and zinc ejection from the peptide will be explored. Oligonucleotides site-specifically modified by a single platinum complex adduct will be used as substrates to study recognition and binding sites. The zinc finger proteins to be studied initially will be the transcription factor Sp1 (Cys2His2 cores) and the repair protein XPA. (Cys4 core). The rates of ligand exchange, the possible incorporation of platinum into the peptide, zinc ejection, and loss of conformation will be evaluated. The fundamental chemistry underlying this metal exchange will be studied by the preparation and structural characterization of model platinum and zinc containing complexes. The possibilities for selective recognition between essential aromatic amino acids and platinated nucleobase compounds through the enhanced pi stacking between platinated nucleobases and tryptophan will be investigated by spectroscopic and computational methods. This project will lead to a deeper understanding of the role of DNA conformation in protein recognition, how the nature of DNA damage affects downstream protein processing and DNA repair and perhaps eventually isolation of DNA-protein adducts in vivo. The broader impacts will be to include undergraduate as well as graduate researchers in the activities. International collaborations with the Czech Republic and Israel will be fostered. The long-term impact of this work for society will be to expand the knowledge base; to challenge in a rational and innovative manner the status of current concepts and to lay the groundwork for development of new medicines.