The broad, long-term objective of this research proposal is to understand the origin of specificity in protein-DNA interactions. Specifically, the research outlined in this proposal involves thermodynamically characterizing E. coil tryptophan repressor protein-DNA interactions and examining the role of water in these binding events. Ultimately, the results of this research will contribute to the information base regarding transcriptional regulation, which will assist in the understanding and treatment of disease states involving transcriptional regulation.