Blog: Halogen bond: definition, modelling and applications

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by: Leonardo Raso Track « Chemoinformatics and Physical Chemistry », Milan-Strasbourg, 2022

Halogens are often being considered as apolar substituents in many organic compounds. Nevertheless, studies in recent years showed that they can have significant interactions with Lewis bases, the so-called halogen bond. [1] This interaction is due to a region of positive electrostatic potential close to the halogen atom. More specifically, this region is situated on the prolongation of the axis which connects the halogen to its neighbor atom and is called σ-hole (Figure 1). The σ-hole can be characterized with three parameters:

  • magnitude, which is the maximum positive value on a chosen isoelectronic surface;
  • size, which is the area of the positive region of the electrostatic potential on a certain isoelectronic surface;
  • extension, which is the distance where the potential goes from positive to null.

In quantum chemistry the σ-hole can be studied using ab initio methods, but these allow to study only small molecules. Nevertheless, it can be interesting to study the role of these interactions in large systems, such as protein-ligand complexes. For these purposes, it is more convenient to use molecular mechanics.

Differently from ab initio methods, the σ-hole must be explicitly integrated in the force field. There exist two approaches to do it. In the simplest one, an extra positive charge is added in proximity of the σ-hole, but this only models the electrostatic properties of the system. The other approach, more accurate, reproduces the anisotropy of the electronic density of the halogen. It uses angle dependent parameters in the Van der Waals and Coulomb terms of the force field.

In protein-ligand interactions halogen bonds can give significant contributions, since each amino acid of a protein has at least one basic function, namely the oxygen in the carbonyl group. Indeed, halogen bond found a place in medicinal chemistry in recent years.

For instance, Zhou and Wong investigated the role of the halogen bond in Haspin kinase using theoretical methods.[2] The authors studied the interaction between the kinase and four halogenated tubercidin ligands and noticed an increasing binding energy for ligands with heavier halogen substituent. This trend supports the thesis that halogen bond may be modulated in a series of halogenated inhibitors. This is an interesting aspect of the halogen bond: its ability to be tuned. The σ-hole parameters highly depend on the nature of the halogen, in particular the heavier is the halogen the bigger are the magnitude and the size of the σ-hole. Also, the scaffold of the ligand plays a role in its properties. Thus, making the halogen bond a versatile tool in medicinal chemistry and drug discovery.

Figure 1: Electrostatic potential projected on a surface of 0.001 au electron density of methane (A), fluoromethane (B), bromomethane (C) and iodomethane (D). Image taken from reference [1].

[1] M. H. Kolář and P. Hobza, “Computer Modeling of Halogen Bonds and Other σ-Hole Interactions,” Chemical Reviews, vol. 116, no. 9. 2016. doi: 10.1021/acs.chemrev.5b00560.
[2] Y. Zhou and M. W. Wong, “Halogen Bonding in Haspin-Halogenated Tubercidin Complexes: Molecular Dynamics and Quantum Chemical Calculations,” Molecules, vol. 27, no. 3, p. 706, Jan. 2022, doi: 10.3390/molecules27030706.