C-X· · ·H Contacts in Biomolecular Systems: How They Contribute to Protein-Ligand Binding Affinity

The hydrogen bond acceptor capability of halogens has long been underappreciated in the field of biology.
In this work, we have surveyed structures of protein complexes with halogenated ligands to characterize
geometrical preferences of C-X· · ·H contacts and contributions of such interactions to protein-ligand binding
affinity. Notably, F · · ·H interactions in biomolecules exhibit a remarkably different behavior as compared to
three other kinds of X· · ·H (X ) Cl, Br, I) interactions, which has been rationalized by means of ab initio
calculations using simple model systems. The C-X· · ·H contacts in biological systems are characterized as
weak hydrogen bonding interactions. Furthermore, the electrophile “head on” and nucleophile “side on”
interactions of halogens have been extensively investigated through the examination of interactions in protein
structures and a two-layer ONIOM-based QM/MM method. In biomolecular systems, C-X· · ·H contacts are
recognized as secondary interaction contributions to C-X· · ·O halogen bonds that play important roles in
conferring specificity and affinity for halogenated ligands. The results presented here are within the context
of their potential applications in drug design, including relevance to the development of accurate force fields
for halogens.