Fig 1.
The side chain structures of the 8 amino acids involved in the salt-bridge and cation-π interactions.
A) The protonated Arg+ is simplified as the NH2CHNH2+ cation. B) The protonated Lys+ is simplified as the CH3NH3 + cation. C) The side chain of acidic amino acid Asp is represented by CH3COOH. D) The side chain of acidic amino acid Glu is represented by C2H5COOH. E) The side chain of the aromatic amino acid Phe is C6H6. F) The side chain of the aromatic amino acid Tyr is C6H5OH. G) The side chain of the aromatic amino acid Trp is the indole ring. H) The side chain of the aromatic amino acid His is the imidazole group. I) The side chain of the amino acid Asn is CH3CONH2. J) The side chain of the amino acid Gln is C2H5CONH2.
Table 1.
The pKa of the three alkaline amino acids (Arg, Lys and His) and the two acidic amino acids (Glu and Asp) [60].
Fig 2.
The salt-bridge interaction structures between three amino acid cations (Arg+ Lys+, and His+) and three acidic amino acids (Asp-, Glu-, and His).
A) The salt-bridge structure of Lys+–Asp-. B) The salt-bridge structure of Lys+–Glu-. C) The salt-bridge structure of Lys+–His. D) The salt-bridge structure of Arg+–Asp-. E) The salt-bridge structure of Arg+–Glu-. F) The salt-bridge structure of Arg+–His. G) The salt-bridge structure of His+–Asp-. H) The salt-bridge structure of His+–Gln-. I) The salt-bridge structure of His+–His. The energies of aa salt bridge interactions are in the range -90 to -520 kJ/mol.
Table 2.
Salt-bridge interaction energies between the two alkaline amino acids (Arg and Lys) and the three acidic amino acids (Glu, Asp and His).
Fig 3.
The cation-π interaction structures between three cations (Arg+, Lys+, and His+) and four aromatic amino acids (Phe, Tyr, Trp, and His).
A) The cation-π interaction structure of Lys+–Phe. B) The cation-π interaction structure of Arg+–Phe. C) The cation-π interaction structure of His+–Phe. D) The cation-π interaction structure of Lys+–Tyr. E) The cation-π interaction structure of Arg+–Tyr. F) The cation-π interaction structure of His+–Tyr. G) The cation-π interaction structure of Lys+–Trp. H) The cation-π interaction structure of Arg+–Trp. I) The cation-π interaction structure of His+–Trp. J) The cation-π interaction structure of Lys+–His. K) The cation-π interaction structure of Arg+–His. L) The cation-π interaction structure of His+–His. The energies of aa cation-π interactions are in the range -50 to -85 kJ/mol.
Table 3.
Cation-π interaction energies between the three cationic amino acids (Arg+, Lys+ and His+) and the four aromatic amino acids (Phe, Try, Trp, and His).
Fig 4.
Amide bridge interactions between amino acids Asn and Gln.
A) Interaction structure of amide bridge for the Asn-Asn interaction. B) Interaction structure of amide bridge for the Asn-Gln interaction. C) Interaction structure of amide bridge for the Gln-Gln interaction. The energies of aa amide bridge interactions are in the range -65 to -70 kJ/mol.
Table 4.
Amide bridge interaction energies between the two amide amino acids (Asn and Gln).
Fig 5.
The structure of the M2 proton channel of influenza A virus (PDB code: 2RLF).
A) Possible binding sites (Ser-31, His-37, Trp-41, and Asp-44) of amantadine. B) The cation-π interaction between amantadine and His-37 in M2 proton channel. C) The salt-bridge interaction between amantadine and Asp-44. D) The cation-π interaction between amantadine and Trp-41.
Fig 6.
The neuraminidase (NA) structure of influenza A virus (PDB code: 1F8B).
A) The binding pocket for ligands in the neuraminidase (NA) of influenza A virus. The hydrophobic pocket consists of 17 residues (Ala118, Leu119, Asn151, Ser152, Leu156, Pro178, Ser198, Met222, Asp224, Ser246, Val247, Trp276, Tyr292, Ile294, Gln371, Leu406, and Phe425). B) The docking structure and salt-bridge interactions of 49 drugs (or ligands) in the binding pocket of neuraminidase (1F8B). There is a formal salt-bridge between the carboxyl group (–COO-) of the ligands and the residue Arg+-371. The other two arginine residues (Arg+-118 and Arg+-292) are on either side of the carboxyl group (–COO-), forming two partial salt-bridge bonds with the oxygen atoms of the carboxyl group. The three salt-bridge bonds are indicated by yellow circles.
Fig 7.
The structure and binding sites of amantadine in p7 ion channel (PDB code: 2M6X) of the hepatitis C virus (HCV).
A) In the p7 channel, the ligand amantadine is in the six hydrophobic pockets consisting of Leu 52, Val 53, Leu55, and Leu 56 from H3 and Phe 20, Val 25, and Val 26 from H2. The hydrophobic residues are shown in green and Trp-21 is shown in white lines. B) The cation-π interaction between the NH3+ group of amantadine and the aromatic indole ring of Trp-21. When Leu20 is replaced by Phe20 (yellow color), the ammonium group (NH3+) of amantadine may shift its orientation and form a cation-π bond with Phe20. This mayreasonably explain the Leu20Phe mutation that confers drug resistance in some p7 channel subtypes. C) The molecular orbital (MO) of the cation-π interaction between the NH3+ group and the aromatic indole ring. The cation perpendicularly points to the π-plane.