B–H⋯π and C–H⋯π interactions in protein–ligand complexes: carbonic anhydrase II inhibition by carborane sulfonamides

Abstract

Among non-covalent interactions, B–H⋯π and C–H⋯π 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–H⋯π hydrogen bonding in a protein–ligand complex. It shows that the B–H⋯π interaction is stabilized by dispersion, followed by electrostatics. Furthermore, it demonstrates that the similar C–H⋯π 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.