Energies and physicochemical properties of cation–π interactions in biological structures

The cation–π interactions occur frequently within or between proteins due to six (Phe, Tyr, Trp, Arg, Lys, and His) of the twenty natural amino acids potentially interacting with metallic cations via these interactions. In this study, quantum chemical calculations and molecular orbital (MO) theory are used to study the energies and properties of cation–π interactions in biological structures. The cation–π interactions of H+ and Li+ are similar to hydrogen bonds and lithium bonds, respectively, in which the small, naked cations H+ and Li+ are buried deep within the π-electron density of aromatic molecules, forming stable cation–π bonds that are much stronger than the cation–π interactions of other alkali metal cations. The cation–π interactions of metallic cations with atomic masses greater than that of Li+ arise mainly from the coordinate bond comprising empty valence atomic orbitals (AOs) of metallic cations and π-MOs of aromatic molecules, though electrostatic interactions may also contribute to the cation–π interaction. The binding strength of cation–π interactions is determined by the charge and types of AOs in the metallic cations. Cation–π interaction energies are distance- and orientation-dependent; energies decrease with the distance (r) and the orientation angle (θ). In solution, the cation–π energies decrease with the increase of the dielectric constant (ɛ) of the solvent; however, solvation has less influence on the H+–π and H3O+–π interactions than on interactions with other cations. The conclusions from this study provide useful theoretical insights into the nature of cation–π interactions and may contribute to the development of better force field parameters for describing the molecular dynamics of cation–π interactions within and between proteins.

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► The energies and properties of cation–π interactions in biological structures are studied using quantum chemistry and molecular orbital theory.
► In the cation–π interactions of H+ and Li+ the small and naked cations are deeply buried in the π–electron density of aromatic motifs, like hydrogen-bond and lithium-bond.
► The cation–π interactions of metallic cations after Li+ arise from the coordinate bond consisting of valence AOs of metallic cations and π–MOs of aromatic molecules.
► The cation–π energies are distance and orientation-dependent that decrease with the distance r and orientation angle θ.
► The cation–π energies decrease with the increase of dielectric constant ɛ of solvents, however, solvation has less effect on the H+–π and H3O+–π interactions.