B-H center dot center dot center dot pi and C-H center dot center dot center dot pi interactions in protein-ligand complexes: carbonic anhydrase II inhibition by carborane sulfonamides

Among non-covalent interactions, B-HMIDLINE HORIZONTAL ELLIPSIS pi and C-HMIDLINE HORIZONTAL ELLIPSIS pi hydrogen bonding is rather weak and less studied. Nevertheless, since both can affect the energetics of protein-ligand binding, their understanding is an important prerequisite for reliable predictions of affinities. Through a combination of high-resolution X-ray crystallography and quantum-chemical calculations on carbonic anhydrase II/carborane-based inhibitor systems, this paper provides the first example of B-HMIDLINE HORIZONTAL ELLIPSIS pi hydrogen bonding in a protein-ligand complex. It shows that the B-HMIDLINE HORIZONTAL ELLIPSIS pi interaction is stabilized by dispersion, followed by electrostatics. Furthermore, it demonstrates that the similar C-HMIDLINE HORIZONTAL ELLIPSIS pi interaction is twice as strong, with a slightly smaller contribution of dispersion and a slightly higher contribution of electrostatics. Such a detailed insight will facilitate the rational design of future protein ligands, controlling these types of non-covalent interactions.

Automated summary

This paper provides the first example of B-H...pi hydrogen bonding in a protein-ligand complex through high-resolution X-ray crystallography and quantum-chemical calculations. The study demonstrates that the B-H...pi interaction is stabilized by dispersion, followed by electrostatics. It also shows that the similar C-H...pi interaction is twice as strong, with a slightly smaller contribution of dispersion and a slightly higher contribution of electrostatics. Such insights will facilitate the rational design of future protein ligands, controlling these types of non-covalent interactions.