CREATION AND INVESTIGATION OF PROTEIN CORE MIMETICS AND DNA BINDING MOLECULES
The goal of this research is to design and synthesize small molecules that mimic structural and functional elements of the zinc finger containing proteins. Two fairly independent areas have been explored to determine stable minimal structure and minimal DNA binding motif of zinc fingers. Mimetic protein cores were created that align a set of L-Phe, D-Phe, or L-Leu residues in a parallel or an antiparallel arrangement in chloroform. Not all cores show a single conformation at room temperature. Stable structures require a synergistic relationship between the H-bonding groups and the residues within the core. The spatial arrangement of the side chains dictates whether a zippered or a crossed pattern of H-bonds is observed for these cores. Variable-temperature 1H NMR experiments were used to determine the strengths of the H-bonds. The existence of H-bonds was verified through FTIR spectroscopic analysis. Large temperature coefficients exist for some protons of aromatic rings that are held in a T-shaped arrangement. A comparison of these temperature coefficients shows that a more stable core is obtained by combining benzenoid and nitrobenzenoid rings as compared to benzenoid rings. Structures were determined using a combination of 2D NMR analysis and molecular modeling. Detailed results of this studies have been published in "Creation and Investigation of Protein - Core Mimetics with Parallel and Antiparallel Aligned Amino Acids", Fotins, J., Smithrud, D. B. J. Org. Chem, Vol. 70, No. 11, 2005. Based on previously studied DNA binding molecules, we have designed second generation mimetic. In addition to a major groove binder already present in the molecule, the mimetic can be derivatized with an intercalator, such as acridine. Functionalization of the aromatic ring provides another attachment point for oligopeptides containing lysine residues, which are known to bind to DNA at the phosphate backbone. Docking experiments performed with HyperChem supported that the overall geometry of the newly designed mimetic is favorable for multiple mode interactions.
School:University of Cincinnati
School Location:USA - Ohio
Source Type:Master's Thesis
Keywords:protein core mimetics zinc finger proteins dna binding
Date of Publication:01/01/2005