Amino-aromatic interactions

Burley, S. K., and Petsko, G. A. (1986). Amino-aromatic interactions in proteins. FEBS Lett. 203, 139-143. 

Fig. 20. Schematic view of the antihyperlipoproteinemic compound bezafibrate bound to deoxyhemoglobin A in the central cavity of the tetramer. The protein-ligand interactions include an amino-aromatic interaction involving asparagine-108 and an aromatic-aromatic interaction involving tryptophan-37, . Reproduced with permission from Perutz et al. (1986).

Like the other weakly polar interactions, amino-aromatic interactions are a mechanism of protein-ligand binding. Perutz et al. (1986) described a series of X-ray crystallographic studies of drugs and peptides bound to deoxy-Hb A. They characterized an amino-aromatic interaction between the 8+ N8—H group of asparagine-108 with the 8 7r-electron cloud of one of the phenyl rings of bezafibrate (see Fig. 20). 

Fig. 25. Stereodrawings of the two conformations of arginine-45 of carbon monoxy-myoglobin from sperm whale, (a) Conformation I, which is comparable to the conformation normally observed in metmyoglobin from sperm whale, (b) Conformation 2, which is stabilized by an amino-aromatic interaction between arginine-45 and phenylalanine-43.

Scrutton, N. S., and Raine, A. R. C., 1996, Cation-tc bonding and amino aromatic interactions in the biomolecular recognition of substituted ammonium ligands, Biochem. J. 319 198. 

Amino/Aromatic Interactions in Proteins—Is the Evidence Stacked Against Hydrogen-Bonding ... 

TMADH showing ionizable residues and the aromatic bowl (Tyr-60, Trp-264 and Trp-355) that interacts with the three methyl groups of the substrate through amino-aromatic interactions. Residues His-172 and Tyr-60 play key roles in stabilising the trimethylamine... 

Two other positively charged residues are located in the pTyr binding pocket of the Src SH2 domain Arg oA2 and Lys pD6 (Fig. 2B). Arg aA2 interacts with the phosphate group and also makes an unusual amino-aromatic interaction with the phenol ring of the pTyr. This type of... 

Another prominent role for cation-n interactions is in stabilizing the secondary structures of proteins. The cationic amino acids Arg and Lys can interact with Phe, Tyr, and Trp in favorable ways. His, if protonated, can serve as the cation of a cation-n interaction, and several studies showed that the pK., of a His side chain can be modulated by a cation-Tc interaction. Neutral His is not a favorable n system for a cation-jr interaction. A pioneering analysis by Burley and Petsko considered the amino-aromatic interaction." in which NH groups from Arg. Lys, Asn. or Gin contact Phe. Tyr. or Trp. It is now appreciated that Arg and Lys are invoh ed in cation-n interactions, while interactions involving Asn or Gin must be polar-n interactions, which are inherently much weaker than cation-n interactions. While this coupling of two different interactions clouded the statistics. " the importance of pointing out the potential for such interactions was substantial. 

Mitchell JB, Nandi CL, McDonald IK, Thornton JM, Price SL. Amino/aromatic interactions in proteins Is the evidence stacked against hydrogen-bonding J Mol Biol. 1994 239 315 31. 

Support for the aromatic h> othesis comes from model studies and protein crystal structure analysis. In biomimetic model studies, Dougherty has shown that cation-x interactions can stabilize both ground and transition states (44), and has used these results to predict the involvement of aromatic sidechains in receptors and enzymes that operate on cationic species (45,46). In the structural realm, the widespread occurrence of amino-aromatic interactions have been noted (47). In addition, a cocrystal structure shows that the myeloma protein McPC603 interacts with tile quaternary ammonium ion of its ligand phosphorylcholine through the... 

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