Metal binding within a peptide-based nucleobase stack with tuneable double-strand topology

Peptide nucleic acid (PNA) oligomers with linear topology are synthesised with histidines at the central positions in order to provide metal-ion coordination sites within the water shielded and non-polar environment of a nucleobase stack that emerges upon duplex formation. Variation of the linker length used for attachment of the nucleobases to the regular peptide backbone allows for fine tuning of the distances and coordination environment at the metal binding site. The effect of zinc and copper incorporation into the modified alanyl-PNA scaffolds on duplex stability was probed by temperature-dependent UV spectroscopy, and additional insight was gained from EPR spectroscopy and EXAFS. Whenever four histidines (two per oligomer strand) are available, addition of Zn2+ significantly enhances double-strand stability, thus supporting coordination of Zn2+ by the histidine-N and incorporation of the metal ion within the base stack. In contrast to Zn2+, however, Cu2+ ions do not induce double-strand formation of an alanyl/norvalyl-PNA oligomer, as confirmed by EPR and EXAFS, which reveal a mixed {N2Ox} donor environment. While metal-ion binding to histidine-modified alanyl-PNA oligomers (and homologues) is apparently feasible, a proper matching of the binding-site geometry and the stereoelectronic requirements of the specific metal ion are essential in order to mediate double-strand formation. This might offer new options for alternative pairing schemes in alanyl-PNA chemistry in which metal coordination substitutes the common base-pair H-bonding pattern, and for metal-dependent regulation of alanyl-PNA duplex formation. ((c) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005).