Cation–π interactions in protein–ligand binding: theory and data-mining reveal different roles for lysine and arginine

, but the empirical distribution of 582 X-ray structures lies away from the minimum on the interaction PES. In contrast, 1381 structures involving arginine match the underlying calculated PES with good agreement. SAPT analysis revealed that underlying differences in the balance of electrostatic and dispersion contributions are responsible for this behavior in the context of the protein environment. The lysine-arene interaction, dominated by electrostatics, is greatly weakened by a surrounding dielectric medium and causes it to become essentially negligible in strength and without a well-defined equilibrium separation. The arginine-arene interaction involves a near equal mix of dispersion and electrostatic attraction, which is weakened to a much smaller degree by the surrounding medium. Our results account for the paucity of cation-π interactions involving lysine, even though this is a more common residue than arginine. Aromatic ligands are most likely to interact with cationic arginine residues as this interaction is stronger than for lysine in higher polarity surroundings.