Strength and Character of Halogen Bonds in Protein-Ligand Complexes

In this study we investigate the strength and character of eight halogen bonding interactions from six protein-ligand complexes. The halogen bonding complexes investigated here were selected because of their favorable halogen bond characteristics. Interaction energies of model systems derived from protein-ligand complexes are computed at the MP2/aug-cc-pVDZ level of theory, and the relative contributions of electrostatics and dispersion are estimated by computing Delta E(HF)/Delta E(MP2) ratios. The relationship between these ratios and DFT-SAPT E-elec/E-disp results is calibrated using smaller model systems in order to gain a qualitative understanding of the relative roles that electrostatics and dispersion play in these halogen bonds. Electrostatic potentials for the halogen bonding ligands are also generated in order to study the relationship between halogen bond strengths and halogen a-hole size (and charge). It is found that the strength and character of the protein-ligand halogen bonds investigated here are strongly dependent on geometric factors and a-hole characteristics. Many of the halogen bonds studied here, especially those with favorable geometric and electrostatic properties, are found to be of sufficient magnitude to make significant contributions to protein-ligand binding.