Quantifying Intramolecular Halogen Bonds in Nucleic Acids: A Combined Protein Data Bank and Theoretical Study.

In this study, we report experimental (Protein Data Bank (PDB) search) and theoretical (RI-MP2/def2-TZVP level of theory) evidence of the nature, stability, and directionality properties of intramolecular halogen bonding interactions (HaBs) between 5-bromo/5-iodoracil bases and backbone phosphate groups in nucleic acids (NAs). A PDB survey revealed relevant examples where intramolecular HaBs are undertaken and serve as a structural source of stability in RNA and DNA molecules. In order to develop suitable energy predictors, we started this investigation by calculating the interaction energy values and both the potential V(r) and kinetic G(r) energy densities (using Bader's "atoms in molecules" theory) of several halogen bond complexes involving 5-bromo/5-iodoracil molecules and biologically relevant electron donors. Once the energy predictors based on V(r)/G(r) energy densities were developed, we analyzed the HaBs observed in the biological examples retrieved from the PDB search in order to estimate the strength of the interaction. As far as our knowledge extends, intramolecular halogen bonds in NAs have not been previously quantified in the literature using this methodology and may be of great importance in understanding their structural properties as well as in the construction of molecular materials with DNA and other biological macromolecules.