Halogen bonds between ligands and proteins: Can we use them in validation?

Halogen bonds are polar interactions between a halogen atom and its acceptor. They have characteristic geometry induced by the positively charged σ-hole on the halogen atom. Despite their importance in drug development, halogen bonds are often overlooked in the analysis and validation of ligand-protein complexes. We analyzed halogen bonds between ligands and proteins in structure models from the PDB-REDO databank and defined key geometric parameters. These are the donor-acceptor distance and two bond angles (θ1 and θ2) for interatomic halogen bonds, or in the case of halogen-π interactions, the distance between the halogen and acceptor π-system and a bond angle (θ1). Based on the distribution of these geometric parameters, we introduce a score, HalBS, that marks whether halogen bonds are adopting the preferred or allowed geometry or are an outlier and should be examined critically. A reference implementation of this score is now available in PDB-REDO and the source code at https://github.com/PDB-REDO/HalBS. This is a first step towards improving halogen bond treatment in the analysis of macromolecular structure models.