Geometric characteristics and energy landscapes of halogen–water–hydrogen bridges at protein–ligand interfaces

Halogen–water–hydrogen bridges (XWH bridges), in which one hydrogen bond (H-bond) in a traditional water-mediated H-bond bridge is replaced by a halogen bond (X-bond), is a novel mode of interaction for water in biological molecules. In this study, we investigate several protein–halogenated ligand complexes using a two-layer quantum mechanics/molecular mechanics (QM/MM) ONIOM method. Analysis of the geometric characteristics and energy behaviors of the complexes, together with the AIM results, indicate that XWH bridges are present in these systems. Furthermore, our investigations show that XWH bridges can have an important role in ligand recognition and binding.