Specific Purine-Purine Base Pairing in Linear Alanyl-Peptide Nucleic Acids

Abstract

Purine-purine base pairing with guanine, isoguanine, 2,6-diaminopurine, and xanthine is investigated within the topology of alanyl-PNA. Alanyl-PNA is based on a regular peptide backbone with alternating configuration of the amino acids. The nucleobases are covalently linked as side chains. Their distance in peptides with β-sheet conformation is similar to the favored base-pair stacking distance. Therefore, alanyl-PNA provides self-pairing linear double-strands. The linear double-strand topology does not restrict base-pair size and geometry. The favored base pairs are formed mostly dependent on recognition by H-bonding. The synthesis of the nucleo-amino acids with unnatural nucleobases and their oligomerization is described. Hexamers and a tetramer based on 2,6-diaminopurine-xanthine and guanine-isoguanine base pairs were observed with very high stabilities. For xanthine-xanthine self-pairing, an unusual tridentate reverse Watson-Crick pairing mode is indicated, that is only possible with xanthines pairing in different tautomeric forms. To investigate the nature of xanthine-xanthine base pairs in more detail, quantum-chemical calculations were performed. They establish the easier tautomerization of xanthine compared to uracil and indicate that, in the AO basis-set limit, the tridentate pairing mode with mixed tautomers is favored.