Sequence-selective interactions of combinatorially generated nickel(II)•Gly-Gly-His derived metallotripeptides with DNA
Abstract
The study presented herein utilizes the DNA cleavage activity of Ni(II)•Xaa 1-Xaa2-His metallopeptides to further our understanding of amino acid interactions with the DNA minor groove. The compounds studied were generated via a parallel combinatorial synthesis strategy that incorporated all naturally occurring L- and D-amino acids, excluding Cys and Trp into the Xaa1-Xaa2-His tripeptide ligand. Also presented are studies that characterized sequence-selective binding of these metallopeptides via a fluorescent intercalator displacement assay. This work found that interactions between the amino acid side chain and the DNA minor groove impact sequence selectivity in a manner dependent upon the α-carbon stereochemistry of Xaa1 = Arg and Lys, but not Pro; similarly, Xaa2 = Arg and Lys substitutions increase cleavage activity and binding affinity, but not sequence selectivity. These results are fully consistent with the proposed model of DNA-bound Ni(II)•Xaa-Xaa-His metallopeptides, as well as ongoing NMR and molecular dynamics studies by this research group. Additionally, the findings parallel the effects of prominent amino acid-minor groove interactions found in Nature, further supporting the use of the Ni(II)•Xaa-Xaa-His metallopeptide template in the investigation of these interactions.
Degree
Ph.D.
Advisors
Long, Purdue University.
Subject Area
Biochemistry
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