Halogen bonds in biological molecules

Abstract

Short oxygen-halogen interactions have been known in organic chemistry 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-X...O-Y interaction (C-X is a carbon-bonded chlorine, bromine, or iodine, and O-Y is a carbonyl, hydroxyl, charged carboxylate, or phosphate group), where the X...O distance is less than or equal to the sums of the respective van der Waals radii (3.27 A for Cl...O, 3.37 A for Br...O, and 3.50 A for I...O) and can conform to the geometry seen in small molecules, with the C-X...O angle approximately 165 degrees (consistent with a strong directional polarization of the halogen) and the X...O-Y angle approximately 120 degrees . 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: (i) the lone pair electrons of oxygen (and, to a lesser extent, nitrogen and sulfur) atoms or (ii) 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.

Fig. 1.

Schematic of short halogen (X) interactions to various oxygen-containing functional groups (where OY can be a carbonyl, hydroxyl, or carboxylate when Y is a carbon; a phosphate when Y is a phosphorus; or a sulfate when Y is a sulfur). The geometry of the interaction is defined by the normalized R_X···O distance [R_X···O = d_X···O/R_{vdW(X···O)}], the Θ₁ angle of the oxygen relative to the CX bond, and the Θ₂ angle of the halogen relative to the OY bond.

Fig. 2.

Ab initio electrostatic potential surfaces of halogenated model compounds. Halogenated methane (X–Me, Top), uridine nucleobase (X⁵U, Middle), and cytosine nucleobase (X⁵C, Bottom) are shown looking into the halogen atoms to compare the induced negative (red), neutral (green), and positive (blue) electrostatic potentials around the halogen surfaces. The potential energies are presented only in the –25 to +25 kcal/mol range to emphasize the variation in electrostatic potential associated with the halogen atoms (note that some regions of electrostatic potential, especially those associated with heteroatoms, may lie beyond this ±25 kcal/mol range). The compounds are ordered (from left to right) from least to most polarizable (F < Cl < Br < I), with the last column showing, for comparison, the potential surface of methane, methylated uridine, and methylated cytosine.

Fig. 3.

Polar scatter plot and histogram distributions for halogen bonds. (a) Polar scatter plot relative to Θ₁ and the normalized halogen (X) to oxygen distances (R_X···O, where R_X···O ≤ R_vdW) are plotted for X&Cl (green circles), XBr (red triangles), and XI (cyan squares). Both the x and y axes of the plot represent R_X···O, with the y axis aligned along the CX bond (180°) and the x axis perpendicular to the CX bond (90°). The shaded region from 90° to 120° indicates the Θ₁ angles that were excluded from our data set. (b) Histogram distribution of Θ₁ angles. The number of short X···O interactions to chlorine (green), bromine (red), and iodine (cyan) halogen atoms, and their sum (gray) are counted and placed into 5° bins of Θ₁ angle and plotted as a 3D histogram. (c) Histogram distribution of Θ₂ angles. This plot is similar to b, except the interactions are placed into 10° bins of Θ₂. (d) Histogram distribution of the dihedral angle Ψ calculated for short halogen bonds involving the OC group of the peptide backbone.

Fig. 4.

Examples of short X···O contacts in a ligand–protein complex and nucleic acids. (a) The 2.2-Å structure (PDB ID code 1P5E) of phospho-CDK2/cyclin A in complex with the inhibitor 4,5,6,7-tetrabromobenzotriazole (27). The inhibitor is shown with three bromine halogen bonds to peptide carbonyl oxygens of the protein. Two interactions (middle) involve the lone pairs of the oxygen atom and one (right) involves the π system of the CO group. In addition, one halogen bond to a water molecule (w) is seen (left). (b) Intramolecular halogen bond identified as stabilizing a DNA junction (PDB ID code 1P54) in the 1.9-Å structure of d(CCAGTACbr⁵UGG) (1). (c) View of the packing interactions involving three short I···O contacts in a unique six-stranded DNA structure (PDB ID code 1UE2; 1.4 Å) of the sequence d(Gi⁵CGAAAGCT) (i⁵C, 5-iodocytosine) (28).