Although fluorination of pharmacologically active compounds has long been a common strategy to increase their metabolic stability and membrane permeation, the functionality of protein-ligand interactions involving fluorine atoms (fluorine bonding) was only recently recognized in the chemistry and biology communities. In this study, the geometric characteristics and the energetic behaviors of fluorine bonding were systematically investigated by combining two quite disparate but complementary approaches: X-ray structural analysis and theoretical calculations. We found that the short contacts involving fluorine atoms (generalized fluorine bonding) between proteins and fluorinated ligands are very frequent, and these contacts, compared to those routine hydrogen/halogen bonding, are more similar to sulfur-involved hydrogen bonding observed in proteins. ONIOM-based quantum mechanics/molecular mechanics analysis further revealed that fluorine bonding does play an essential role in protein-ligand binding, albeit the strength of isolated fluorine bonding is quite modest. Furthermore, 14 quantum mechanics (QM) and molecular mechanics (MM) methods were performed to reproduce fluorine bonding energies obtained at the rigorous MP2/aug-cc-pVDZ level of theory, and the results showed that most QM and very few MM methods perform well in the reproducibility; the MPWLYP functional and MMFF94 force field are recommended to study moderate and large fluorine bonding systems, respectively.

Halogen bonding, a specific intermolecular noncovalent interaction, plays crucial roles in fields as diverse as molecular recognition, crystal engineering, and biological systems. This paper presents an ab initio investigation of a series of dimeric complexes formed between bromobenzene and several electron donors. Such small model systems are selected to mimic halogen bonding interactions found within crystal structures as well as within biological molecules. In all cases, the intermolecular distances are shown to be equal to or below sums of van der Waals radii of the atoms involved. Halogen bonding energies, calculated at the MP2/aug-cc-pVDZ level, span over a wide range, from -1.52 to -15.53 kcal/mol. The interactions become comparable to, or even prevail over, classical hydrogen bonding. For charge-assisted halogen bonds, calculations have shown that the strength decreases in the order OH- > F- > HCO2- > Cl- > Br-, while for neutral systems, their relative strengths attenuate in the order H2CS > H2CO > NH3 > H2S > H2O. These results agree with those of the quantum theory of atoms in molecules (QTAIM) since bond critical points (BCPs) are identified for these halogen bonds. The QTAIM analysis also suggests that strong halogen bonds are more covalent in nature, while weak ones are mostly electrostatic interactions. The electron densities at the BCPs are recommended as a good measure of the halogen bond strength. Finally, natural bond orbital (NBO) analysis has been applied to gain more insights into the origin of halogen bonding interactions.