Halogenation of nucleic acid structures: from chemical biology to supramolecular chemistry

Abstract

Halogenation of organic molecules is a widespread resource used in the fields of chemical biology and rational drug design to improve the binding affinity or solubility of a given compound. Interestingly, the incorporation of Br and I in DNA/RNA bases has been routinely carried out during decades to facilitate the structural determination of nucleic acids, without accounting for its impact in the DNA/RNA structure and molecular recognition events involving other biological entities (e.g. proteins and peptides). This is of critical importance, since halogens undergo non-covalent binding (specially Br and I) through the formation of halogen bonding interactions, thus structurally influencing peptide/protein–DNA/RNA binding poses or altering the supramolecular architecture of isolated nucleic acid structures. In this review, the physical nature of halogen bonds involving nucleobases as well as their implications in (i) the formation of protein–DNA/RNA complexes and (ii) the stabilization of non-canonical DNA/RNA structures will be discussed, focusing on the role of this non-covalent interaction as a promising tool in nucleic acid chemistry.