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 COX⅐⅐⅐OOY interaction (COX is a carbon-bonded chlorine, bromine, or iodine, and OOY is a carbonyl, hydroxyl, charged carboxylate, or phosphate group), where the X⅐⅐⅐O distance is less than or equal to the sums of the respective van der Waals radii (3.27 Å for Cl⅐⅐⅐O, 3.37Å for Br⅐⅐⅐O, and 3.50 Å for I⅐⅐⅐O) and can conform to the geometry seen in small molecules, with the COX⅐⅐⅐O angle Ϸ165°(consistent with a strong directional polarization of the halogen) and the X⅐⅐⅐OOY angle Ϸ120°. 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 -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. molecular folding ͉ molecular recognition ͉ molecular design T wo recent biomolecular single-crystal structures, a fourstranded DNA Holliday junction (1) and an ultrahighresolution structure (0.66 Å) of the enzyme aldose reductase complex with a halogenated inhibitor (2), revealed unusually short Br⅐⅐⅐O contacts [Ϸ3.0 Å, or Ϸ12% shorter than the sum of their van der Waals radii (R vdW )]. The atypical contact in the enzyme complex was attributed to an electrostatic interaction between the polarized bromine and the lone pair electrons of the oxygen atom of a neighboring threonine side chain (3). Short halogen-oxygen interactions are not in themselves new: The chemist Odd Hassel (4) had earlier described Br⅐⅐⅐O distances as short as 2.7 Å (Ϸ20% shorter than R vdW ) in crystals of Br 2 with various organic compounds.These short contacts, originally called charge-transfer bonds, were attributed to the transfer of negative charge from an oxygen, nitrogen, or sulfur (a Lewis base) to a polarizable halogen (a Lewis acid) (5, 6). They are now referred to as halogen bonds (Fig. 1) by analogy to classical hydrogen bonds with which they share numerous properties (6) and are currently being exploited to control the crystallization of organic compounds in the design of new materials (7) as well as in supramolecular chemistry (6). Extensive surveys of structures in the Cambridge Structural Database (8-10) coupled with ab initio calculations (10) have characterized the geometry of halogen bonds in small molecules and show that the interaction is primarily electrostatic, with contributions from polar...

Structure-Based Engineering of Internal Cavities in Coiled-Coil Peptides,

“…These volume increases result from greater N-terminal interhelical distances (described below), and likely take place to allow the most enthalpically favorable packing interactions between the host assembly and guest molecule. The plane of the iodobenzene aromatic ring is more tilted with respect to the long bundle axis in L9A+IB than in L9G+IB, which is likely due to the tighter packing in the smaller cavity.The polarizable iodine atom of the bound iodobenzene is projected toward and potentially forms polar contacts with the backbone nitrogen of Gly9 (3.90 Å interatomic distance) and the backbone carbonyl oxygen of Ile5 (3.82 Å interatomic distance) (Figures 5a, S1a), consistent with previous reports of polar interactions between halogen atoms and proteins (46,47). The L9G+IB and L9A+IB structures also contain new water molecules inside and near the periphery of the channel between the ligand and bulk solvent, which may be explained by the increased size of the cavity ( Figure S1b).…”

Isomorphous Crystals from Diynes and Bromodiynes Involved in Hydrogen and Halogen Bonds

“…This is also supported by the alignment of the four atoms C-Br¨¨¨O=C matching that of the C-H¨¨¨O=C atoms involved in a hydrogen bond [53]. Few examples of such halogen bonds are reported in the Cambridge Structural Database [26,[54][55][56]. strongly suggesting that there is more at stake than a simple van der Waals contact between the two heteroatoms.…”

“…This is also supported by the alignment of the four atoms C-Br···O=C matching that of the C-H···O=C atoms involved in a hydrogen bond [53]. Few examples of such halogen bonds are reported in the Cambridge Structural Database [26,[54][55][56]. Finally, for both crystals, slow degradation occurs over time at room temperature and in ambient atmosphere.…”

“…Scientists exploit supramolecular chemistry (bottom-up strategy) to achieve this goal and control the organization of molecules into diverse 1D [2][3][4], 2D [5][6][7][8][9] or 3D shapes [10][11][12]. Owing to their directional potential, hydrogen bond [13][14][15][16][17][18][19][20][21][22][23] or halogen bond [24][25][26][27][28][29][30][31][32][33][34][35][36] are intermolecular forces that are often used to stick molecular building blocks together. Recently, in our laboratories, we exploited mainly H bonds to build supramolecular walls based on lactams [37] or proline derivatives [38].…”

The shape of the halogen atom—anisotropy of electron distribution and its dependence on basis set and method used

“…Among different noncovalent interactions, the halogen bond (X-bond) attracts particular attention of researchers because, similarly as the hydrogen bond (H-bond), it is responsible for physical, chemical, and biologic properties of a large group of chemical species [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]. The X-bond is of the strength close to that of H-bond [1] and is strongly directional [17].…”