Biological halogen bonds in protein-ligand complexes: a combined QTAIM and NCIPlot study in four representative cases

In this study, the PDB has been manually scrutinized by using a subset of all PDB entries containing organic iodinated ligands. Four structures exhibiting short IMIDLINE HORIZONTAL ELLIPSISA halogen bonding (HaB) contacts (A stands for the sigma-hole acceptor) have been selected and further analysed. In most hits, the sigma-hole acceptor corresponds to an O-atom of the amido group belonging to the protein backbone. In a minority of hits, the electron donors are O, S, Se or pi-systems of the amino-acid side chains. A judicious selection of four PDB structures presenting all four types of HaB interactions (C-IMIDLINE HORIZONTAL ELLIPSISA, A = O, S, Se, pi) has been performed. For these selected structures, a comprehensive RI-MP2/def2-TZVP study has been carried out to evaluate the HaB energetically. Moreover, the interactions have been characterized by combining the quantum theory of atoms-in-molecules (QTAIM) and the noncovalent interaction plot (NCIPlot) and rationalized using the molecular electrostatic potential (MEP) surface.

Automated summary

In this study, a comprehensive analysis was conducted on four PDB structures showing halogen bonding (HaB) interactions, with the sigma-hole acceptor mainly corresponding to O atoms from the protein backbone or amino-acid side chains. RI-MP2/def2-TZVP study was performed to evaluate the energetics of HaB, while QTAIM, NCIPlot, and MEP were used to characterize and rationalize the interactions.