Although recognized in small molecules for quite some time, the implications of halogen bonding in
biomolecular systems are only now coming to light. In this study, several systems of proteins in complex
with halogenated ligands have been investigated by using a two-layer QM/MM ONIOM methodology. In
all cases, the halogen-oxygen distances are shown to be much less than the van der Waals radius sums.
Single-point energy calculations unveil that the interaction becomes comparable in magnitude to classical
hydrogen bonding. Furthermore, we found that the strength of the interactions attenuates in the order H ¡Ö
I > Br > Cl. These results agree well with the characteristics discovered within small model halogenbonded
systems. A detailed analysis of the interactions reveals that halogen bonding interactions are
responsible for the different conformation of the molecules in the active site. This study would help to
establish such interaction as a potential and effective tool in the context of drug design.