Cation-π interactions in structural biology

Abstract

Cation-interactions in protein structures are identified and evaluated by using an energy-based criterion for selecting significant sidechain pairs. Cation-interactions are found to be common among structures in the Protein Data Bank, and it is clearly demonstrated that, when a cationic sidechain (Lys or Arg) is near an aromatic sidechain (Phe, Tyr, or Trp), the geometry is biased toward one that would experience a favorable cation-interaction. The sidechain of Arg is more likely than that of Lys to be in a cation-interaction. Among the aromatics, a strong bias toward Trp is clear, such that over one-fourth of all tryptophans in the data bank experience an energetically significant cation-interaction.The three-dimensional structure of a protein is determined by a delicate balance of weak interactions. Hydrogen bonds, salt bridges, and the hydrophobic effect all play roles in folding a protein and establishing its final structure. In addition, the cation-interaction (1-3) is increasingly recognized as an important noncovalent binding interaction relevant to structural biology. Theoretical and experimental studies have shown that cation-interactions can be quite strong, both in the gas phase and in aqueous media. A number of studies have established a role for cation-interactions in biological recognition, especially in the binding of acetylcholine (4, 5). Here we present a detailed analysis of the extent and nature of cation-interactions that are intrinsic to a protein's structure and likely contribute to protein stability. We find that energetically significant cation-interactions are common in proteins-a ''typical'' protein will contain several. We also have documented some significant preferences for certain amino acid pairs as partners in a cation-interaction.Important early work indicated a role for cation-interactions in protein structures. Following work by Levitt and Perutz (6-8) suggesting a hydrogen bond between aromatic and amino groups, Burley and Petsko identified the ''amino aromatic'' interaction (9), in which NH-containing groups tend to be positioned near aromatic rings within proteins. It is now appreciated that the interaction of a cationic group with an aromatic-a cation-interaction-is much more favorable than an analogous interaction involving a neutral amine (10, 11). Important subsequent studies by Thornton (12-17) modified the Burley and Petsko analysis, especially with regard to the amino-aromatic ''hydrogen bond.'' In addition, explicit studies of Arg interacting with aromatic residues have been reported by Flocco and Mowbray (18) and by Thornton (14), and other efforts to search the Protein Data Bank (PDB) for cation-interactions between ligands and proteins have been reported (19,20).Previous protein database searches relied on geometric definitions of sidechain interactions, focusing on when a cationic sidechain displayed a certain distance͞angle relationship to an aromatic sidechain. The different geometries of Lys vs. Arg and Trp vs. Phe͞Tyr can make such comparisons proble...

Aromatic interactions at the catalytic subsite of sucrose phosphorylase: Their roles in enzymatic glucosyl transfer probed with Phe52 → Ala and Phe52 → Asn mutants

“…1) and the apparent amount of stabilization energy derived from the proposed interaction (Fig. 2) would be in useful agreement with literature on geometrical and energetic features of the cation-p interaction [32][33][34][35]. However, interpretation of kinetic consequences resulting from site-directed substitutions of Phe 52 in terms of loss of local interaction energy must be made with caution.…”

Trp fluorescence reveals an activation‐dependent cation‐π interaction in the Switch II region of Gαi proteins

“…2(A,B)]. A computational study of energetically favorable cation-p interactions determined that the CD and CZ atoms of Arg (d-carbon and guanidinium carbon, respectively) are typically within 6 Å of the aromatic ring of Trp, 28 as is the case here [ Fig. 2(A)].…”

“…1), which allosterically link the Switch II region to activation-dependent changes in the nucleotide binding site. Computational analysis using the program CaPTURE 28 estimates the strength of this interaction to be approximately À2.0 kcal/mol, which reflects both electrostatic and van der Waals contributions, resulting in an energetically relevant interaction between these residues.…”

Fragmentation of phosphopeptides by atmospheric pressure MALDI and ESI/ion trap mass spectrometry

“…Alternatively, it may be that the arginine and lysine side chains are interacting directly with the -cloud of the phosphotyrosine phenyl ring in a cation-interaction, thus facilitating gas phase phosphate fragmentation [25][26][27]. Crystal structures of various SH2 domain phosphotyrosine-peptide complexes depict interactions between the aromatic ring of phosphotyrosine and positively charged residues [26].…”