Halogen bonds in biological molecules

Short oxygen-halogen interactions have been known in organicchemistry since the 1950s and recently have been exploited in the design of supramolecular assemblies. The present survey of protein and nucleic acid structures reveals similar halogen bonds as potentially stabilizing inter- and intramolecular interactions that can affect ligand binding and molecular folding. A halogen bond in biomolecules can be defined as a short C-(XO)-O-....-Y interaction (C-X is a carbon-bonded chlorine, bromine, or iodine, and O-Y is a carboryl, hydroxyl, charged carboxylate, or phosphate group), where the X.. 0 distance is less than or equal to the sums of the respective van der Waals radii (3.27 Angstrom for (ClO)-O-...., 3.37Angstrom for Br...O, and 3.50 Angstrom for I....O) and can conform to the geometry seen in small molecules, with the C-X....O angle approximate to165degrees (consistent with a strong directional polarization of the halogen) and the X.. O-Y angle approximate to120degrees. Alternative geometries can be imposed by the more complex environment found in biomolecules, depending on which of the two types of donor systems are involved in the interaction: (1) the lone pair electrons of oxygen (and, to a lesser extent, nitrogen and sulfur) atoms or (it) the delocalized pi-electrons of peptide bonds or carboxylate or amide groups. Thus, the specific geometry and diversity of the interacting partners of halogen bonds offer new and versatile tools for the design of ligands as drugs and materials in nanotechnology.