Halogen bonding (X-bonding): a biological perspective

Abstract

The concept of the halogen bond (or X-bond) has become recognized as contributing significantly to the specificity in recognition of a large class of halogenated compounds. The interaction is most easily understood as primarily an electrostatically driven molecular interaction, where an electropositive crown, or σ-hole, serves as a Lewis acid to attract a variety of electron-rich Lewis bases, in analogous fashion to a classic hydrogen bonding (H-bond) interaction. We present here a broad overview of X-bonds from the perspective of a biologist who may not be familiar with this recently rediscovered class of interactions and, consequently, may be interested in how they can be applied as a highly directional and specific component of the molecular toolbox. This overview includes a discussion for where X-bonds are found in biomolecular structures, and how their structure-energy relationships are studied experimentally and modeled computationally. In total, our understanding of these basic concepts will allow X-bonds to be incorporated into strategies for the rational design of new halogenated inhibitors against biomolecular targets or toward molecular engineering of new biological-based materials.

Figure 1

Hydrogen and halogen bonds. The geometries and types of donor and acceptor atoms are compared for classic hydrogen bonds (H-bonds) and halogen bonds (X-bonds) seen in biomolecular systems. Each interaction is characterized as being shorter than the sum of the van der Waals radii (∑r_vdW) of the respective atoms. The halogen of the X-bond is shown with the electropotential polarized from positive (blue) to neutral (green) to negative (red). The approach of the acceptor to the halogen and halogen to the acceptor are labeled as θ₁ and θ₂, respectively. Acceptors that include the delocalized electrons of the amide peptide bond or the ring of an aromatic amino acid are listed as π.

Figure 2

The σ-hole model and polarization of the electrostatic surface potential. The σ-hole resulting from redistribution of the valence electron in the p_z-atomic orbital (blue) to form the covalent C-X σ-bond (yellow) of a halomethane (X-Me) molecule results in depopulation of the p_z orbital, but maintaining the electrons of the p_x and p_y orbitals (red). The resulting polarization of the electrostatic potential of the halogen surfaces increases as the size of the halogen increases, from F to Cl to Br to I (viewed down the X-C bond). The halogen attached to a more electronegative molecule (e.g., a uracil base, XU) exaggerates the polarization effects. Electrostatic potential surfaces were calculated by DFT calculations at the 3-21G* level.

Figure 3

Tunability of halogen bonding energies. MP2 calculations at the 6-31G(d) level compares the effects on the energies (△E) for bromobenzene (Brϕ) interacting with the carbonyl oxygen of N-methyl acetamide (NMA) in the gas phase (A) as the bromine is replaced by a less polarizable chlorine (B), with electron-withdrawing fluorine substituents added to the Brϕ donor (C), an electron donating methyl added to the NMA acceptor (D), or as it is transferred to solvent (cyclohexane, with a dielectric constant = 2.023, panel E).

Figure 4

Survey of X-bonds in the PDB. Number of interactions at distances ≤Σr_vdW were tabulated for acceptor types that can only form X-bonds, including oxygens, nitrogens, and sulfurs and H-bond donors from θ₁ = 140°–180° (up to the neutral point of the electrostatic potential). (A) Number of X-bonds to Cl (477 total), Br (157 total), and I (130 total), normalized for total number of observations for each type of halogen, and the total of these normalized observations. The X-bond distribution is centered at θ₁ ≈ 160° for all halogen types. (B) Distribution of distances between X-bond donors and acceptors as percentages of the Σr_vdW (%Σr_vdW).

Figure 5

Recognition of 3,5,3′-triiodothyroxine (T3) by human thyroid hormone receptor. X-bonds (dotted lines) are shown from two iodines (purple) of T3 to the carbonyl oxygens (red) of the peptide bonds of the receptor, along with the distances and θ₁ angles for each interaction (PDB-ID 2H7947).

Figure 6

Four-stranded DNA junction as a competitive assay for H-bonding versus X-bonding energies. A four-stranded junction composed of unique DNA strands can isomerize to place either cytosine bases to form stabilizing H-bond (cyan strands) or 5-bromouracil (BrU) bases to form stabilizing X-bonds (magenta strands) to the sharp U-turn of the junction cross-over, adopting the H-isomer and X-isomer forms, respectively. In the X-isomer, the two possible BrU···OPO₃⁻¹ interactions have energies that are 2–5 kcal/mol more stabilizing than the competing H-bonds.

Figure 7

Comparison of halogenated and nonhalogenated inhibitors to protein targets. Cathepsin L in complex with the nonhalogenated ligand (2S,4R)-4-(2-chlorophenyl)sulfonyl-N-[1-(iminomethyl)cyclopropyl]-1-[1-(4-methylphenyl)cyclopropyl]carbonyl-pyrrolidine-2-carboxamide (A, PDB-ID 2XU561) and its iodinated analog (B, PDB-ID 2YJ862). Complex of cyclin kinase CK2 with 1H-indazole (C, PDB-ID 2VTA63) is compared with casein kinase CK2 bound to tetrabromobenzimidazole (D, 2OXY64). The polypeptides backbone are traced as a green ribbon, with amino acids and ligands involved in X-bonding interactions (black dashes) shown as ball stick models with carbons (gray), oxygen (red), nitrogen (blue), iodine (purple), and bromine (brown). The affinities of each ligand are labeled in terms of their IC50 or K_i values.

Figure 8

Number of X-bond publications from 1990 to 2012. The number of publications with the words “halogen” and “bond” in the title as found in SciFinder (gray bars) is compared with the number of citations to the publication of Metrangolo et al. (as a measure of interest in the material chemistry literature, black bars) and of citations to the publication of Auffinger et al. (as a measure of interest in the biological literature, white bars). The horizontal dashed line indicates the average number of publications per year in which “halogen” and “bond” appear in SciFinder, but are not related to X-bonds. The biological literature has accounted for at least half the publications on X-bonds since 2007.