The Effects of Protein Environments on the Geometries and Energies of Hydrogen Bond Enhanced Halogen Bonds.

Halogen bonds (XBs) are significant interactions in protein-inhibitor complexes. The XB potentials of halogens are greatly influenced by hydrogen bonds (HBs) through synergistic HB enhanced halogen bond (HBeXB) interactions. In this survey of the Protein Data Bank, we find that HBeXBs constitute ∼45% of all XBs, although their overall geometries are similar to those of XBs alone. However, shorter HBs are seen to correlate with more linear XBs. Uncharged HB donors increase the electrostatic surface potentials (ESPs) of HBeXB models by 2-10 kcal/mol, while ESPs with charged donors increase by 55-65 kcal/mol. This charge effect on ESPs translates to an increase in interaction energy of 5-6 kcal/mol. Finally, IC50s for a limited set of halogenated inhibitors appear to be associated with HB angles of approach. Thus, HBs significantly influence the geometries and energies of HBeXBs, providing insights useful for the design of more effective therapeutic inhibitors.