Published: June 02, 2011 r2011 American Chemical Society 6083 dx.doi.org/10.1021/ic200138b | Inorg. Chem. 2011, 50, 6083–6092 ARTICLE pubs.acs.org/IC Metal Binding to Ligand-Containing Peptide Nucleic Acids Zhijie Ma, † Frank Olechnowicz, † Yury A. Skorik, ‡ and Catalina Achim* ,† † Department of Chemistry, Carnegie Mellon University, 4400 Fifth Avenue, Pittsburgh, Pennsylvania 15213, United States ‡ Department of Pharmaceutical Engineering, St. Petersburg State Chemical Pharmaceutical Academy, 14 Prof. Popov Street, St. Petersburg, 197376 Russian Federation b S Supporting Information ABSTRACT: The substitution of nucleobases in nucleic acid duplexes with ligands that have high affinity for transition metal ions creates metal- binding sites at specific locations within the duplexes. Several studies on the incorporation of metal ions into DNA and peptide nucleic acid (PNA) duplexes have suggested that the stability constant of the metal complex formed within the duplexes is a primary determinant of the thermal stability of the duplexes. To understand this relationship, we have synthesized two PNA monomers that carry the same ligand, namely 8-hydroxyquinoline, but have this ligand attached differently to the PNA backbone. The PNA monomers have been incorporated into PNA duplexes. UV and CD spectroscopy and calorimetric studies of the 8-hydro- xyquinolinePNA duplexes showed that the effect of the stability of the metal complex on the PNA duplexes was significantly modulated by the steric relationship between the complex and the duplex. This information is useful for the construction of hybrid inorganicnucleic acid nanostructures. ’ INTRODUCTION The interaction between nucleic acids and transition metal ions can be used to create molecules that have potential applica- tions in nanotechnology and molecular electronics. 1 A strategy for metal ion incorporation into nucleic acid duplexes first proposed by Tanaka and Shionoya in 1999 involves the replacement of the natural nucleobases by ligands that have a higher affinity for metal ions than the natural nucleobases (Scheme 1). 2 The metal complexes formed with these ligand-modified, nucleic acid du- plexes can function as metal-mediated, alternative base pairs. If the ligands are aromatic and the geometry of the metal complex is planar, the complexes can participate in π-stacking interactions with adjacent nucleobase pairs. This strategy allows the incorpora- tion of metal ions at specific positions in a nucleic acid duplex, 1,3,4 as well as the creation of arrays of metal ions within a duplex. 5 In the past decade, numerous ligands have been introduced into DNA, RNA, LNA, PNA, and GNA oligomers, and a variety of metal ions have been incorporated into the ligand-modified duplexes formed by these oligomers. 1,3,4,6 Work in our lab focuses on the use of PNA as a scaffold for metal ions. PNA is a synthetic analogue of DNA that commonly has a backbone based on N-(2-aminoethyl)-glycine (Aeg). 7 PNA exhibits a remarkable affinity for complementary DNA and RNA, because its backbone is neutral. In our previous research, methyl bipyridine, bipyridine (Bipy), and 8-hydroxyquinoline (Q) have been introduced into PNA oligomers that formed PNA duplexes containing Ni 2þ , Co 2þ , or Cu 2þ . 810 We determined that the thermal stability of the metal-containing, bipyridinePNA du- plexes correlates with the stability constant of the corresponding metal complexes, 8 which is in agreement with results obtained in studies of metal incorporation into DNA duplexes. 4 For example, DNA duplexes containing 2 0 -deoxyribosyl-N9-[6-(2 0 pyridyl)- purine)] (Pur p ) or 2 0 -deoxyribosyl-N1-[4-(2 0 pyridyl)-pyrimidi- none)] (Pyr p ) have been stabilized in the presence of Ni 2þ to approximately the same extent despite the fact that the geometry of the Ni 2þ Pur p complex can match that of the base pair in DNA, while the Ni 2þ Pyr p complex has a geometry dissimilar from that of the base pair (Scheme 2a,b). 11,12 The high stability of the duplex that contains the Ni 2þ Pyr p complex was attrib- uted to the strong coordination bonds and the stacking interac- tions that occur between the ligands and base pairs and may Received: January 20, 2011