Halogen Bonding in Nucleic Acid Complexes

TL;DR

This paper provides a comprehensive analysis of halogen bonding in nucleic acid complexes, highlighting the prevalence of X-bonds with nucleobases and identifying gaps in ligand interactions.

Contribution

It is the first detailed study of halogen bonds in nucleic acid complexes, focusing on structural analysis and identifying potential for novel nucleic acid binders.

Findings

Phosphate backbone oxygen is the most common halogen acceptor.

21 X-bonds identified in nucleic acid structures.

Most X-bonds involve halogenated nucleobases with good geometries.

Abstract

Halogen bonding (X-bonding) has attracted notable attention among noncovalent interactions. This highly directional attraction between a halogen atom and an electron donor has been exploited in knowledge-based drug design. A great deal of information has been gathered about X-bonds in protein-ligand complexes, as opposed to nucleic acid complexes. Here we provide a thorough analysis of nucleic acid complexes containing either halogenated building blocks or halogenated ligands. We analyzed close contacts between halogens and electron-rich moieties. The phosphate backbone oxygen is clearly the most common halogen acceptor. We identified 21 X-bonds within known structures of nucleic acid complexes. A vast majority of the X-bonds is formed by halogenated nucleobases, such as bromouridine, and feature excellent geometries. Noncovalent ligands have been found to form only interactions with suboptimal interaction geometries. Hence, the first X-bonded nucleic acid binder remains to be discovered.