DNA Recognition by Peptide Complexes of Rhodium(III): Example of a Glutamate Switch
A family of metal-peptide complexes has been synthesized by coupling short oligopeptides (13 residues) onto the metallointercalating [Rh(phi)_2(phen')]^(3+) (phi = 9,10-phenanthrenequinone diimine; phen' = 5-(amidoglutaryl)-1,10-phenanthroline). These complexes were prepared to explore whether the side-chain functionalities of small peptides may be used to augment metal complex recognition. The metal-peptide complexes bind and, with photoactivation, cleave DNA. The DNA site-specificity is seen to depend on the peptide side-chain functional groups. In particular, a single glutamate at position 10 is found to be essential in directing DNA site-recognition to the sequence 5'-CCA-3'. Methylation of the glutamate side chain or direct substitution of glutamine for glutamate abolishes the 5'-CCA-3' selectivity, while substitutions at other likely DNA-binding residues show no appreciable change in selectivity. Significantly, the 5'-CCA-3' selectivity is even sensitive to a highly conservative E10D substitution. DNA photocleavage of oligonucleotides by the metal-peptide complexes and HPLC analysis of DNA products provide evidence for major groove chemistry. Circular dichroism indicates significant α-helical content in the peptide, which depends upon the presence of the glutamate. A model for the glutamate-dependent site-selectivity is presented using shape-selective intercalation of the metal complex and base-specific contacts of the ancillary peptide. These monomeric metal-peptide complexes appear to serve as particularly useful mimics for larger site-specific DNA-binding proteins and may provide a basis for the design of an array of small, sequence-specific DNA-binding metal complexes.
© 1994 American Chemical Society. Received January 20, 1994. We are grateful to American Cyanamid for their financial support in this research. We also thank Glaxo (N.Y.S.) and the Swiss National Science Foundation (K.Z.) for fellowship support. In addition we thank the Biopolymer Synthesis and Analysis Resource Center at Caltech for their technical assistance.