In drug design and enzyme engineering, the information of interactions between receptors and ligands is crucially
important. In many cases, the protein structures and drug-target complex structures are determined by a delicate
balance of several weak molecular interaction types. Among these interaction forces several unconventional interactions
play important roles, however, less familiar for researchers. The cation-π interaction is a unique noncovalent interaction
only acting between aromatic amino acids and organic cations (protonated amino acids) and inorganic cations (proton and
metallic). This article reports new study results in the interaction strength, the behaviors and the structural characters of
cation-π interactions between aromatic amino acids (Phe, Tyr, and Trp) and organic and inorganic cations (Lys+, Arg+, H+,
H3O+, Li+, Na+, K+, Ca2+, and Zn2+) in gas phase and in solutions (water, acetonitrile, and cyclohexane). Systematical research
revealed that the cation-π interactions are point-to-plane (aromatic group) interactions, distance and orientationdependent,
and the interaction energies change in a broad range. In gas phase the cation-π interaction energies between
aromatic amino acids (Phe, Tyr, and Trp) and metallic cations (Li+, Na+, K+, Ca2+, and Zn2+) are in the range -12 to -160
kcal/mol, and the interaction energies of protonated amino acids (Arg+ and Lys+) are in the range from -9 to -18 kcal/mol.
In solutions the cation-π energies decrease with the dielectric constant ε of solvents. However, in aqueous solution the
cation-π energies of H3O+ and protonated amino acids are less affected by solvation effects. The applications of unconventional
interaction forces in drug design and in protein engineering are introduced.