The M2 protein from influenza A virus is a tetrameric ion channel. It was reported that the permeation of
the ion channel is correlated with the hydrogen bond network among His37 residues and the cation-π
interactions between His37 and Trp41. In the present study, the hydrogen bonding network of
4-methyl-imidazoles was built to mimic the hydrogen bonds between His37 residues, and the cation-π
interactions between 4-methyl-imidazolium and indole systems were selected to represent the interactions
between His37 and Trp41. Then, quantum chemistry calculations at the MP2/6-311G** level were
carried out to explore the properties of the hydrogen bonds and the cation-π interactions. The calculation
results indicate that the binding strength of the N—H···N hydrogen bond between imidazole rings is
up to −6.22 kcal·mol−1, and the binding strength of the strongest cation-π interaction is up to −18.8
kcal·mol−1 (T-shaped interaction) or −12.3 kcal·mol−1 (parallel stacking interaction). Thus, the calculated
binding energies indicate that it is possible to control the permeation of the M2 ion channel
through the hydrogen bond network and the cation-π interactions by altering the pH values.