A Computational Study of Cation−π Interactions vs Salt Bridges in Aqueous Media:  Implications for Protein Engineering

Abstract

A direct comparison of the energetic significance of a representative salt bridge vs a representative cation-π interaction in aqueous media and in a range of organic solvents is presented using ab initio electronic structures and the SM5.42R/HF solvation model of Cramer and Truhlar. The cation-π interaction shows a well depth of 5.5 kcal/mol in water, significantly larger than the 2.2 kcal/mol seen for the salt bridge. Consistent with this idea, a survey of the Protein Data Bank reveals that energetically significant cation-π interactions are rarely completely buried within proteins, but prefer to be exposed to solvent. These results suggest that engineering surface-exposed cation-π interactions could be a novel way to enhance protein stability.

Naphthyl-Containing Organophosphonate Derivatives of Keggin-Type Polyoxotungstates

“…Bond Valence Sum Calculations (BVS) [55] The relative arrangement of the naphthyl residues allows the insertion of a bulky TBA cation (N1 and N4), in such a way that this results embraced between the two aromatic systems via nonconventional cation¨¨¨π [56] and C-H¨¨¨π type interactions [57] (Figure 2E). The distances of the C atoms from the TBA cations to the ring centroids (3.683(4)-4.188(6)Å) compare well with those calculated in the literature for such type of C-H¨¨¨π contacts [58]. The crystal packing displays a pronounced two-dimensional character with hybrid anions linked through C-H¨¨¨O POM hydrogen bonds in bilayers that stack along the [001] direction.…”

Molecular mechanism of pH-dependent substrate transport by an arginine-agmatine antiporter

“…The second class comprises the aromatic amino acids Phe, Tyr, and Trp. These aromatic residues may sense protons through cation-π interactions, which are known to be considerably stronger than hydrogen bonds (19)(20)(21). The third class also includes three types of amino acids, Ser, Thr, and Cys, which have slightly basic pK a but theoretically might still serve as a pH sensor in certain circumstances.…”

Analysis of the Structural and Molecular Basis of Voltage-sensitive Sodium Channel Inhibition by the Spider Toxin Huwentoxin-IV (μ-TRTX-Hh2a)

“…It is well known that cation-interactions on the surface of proteins have a stabilizing effect on structure; however, we conclude based on our NMR data that mutations in Trp 30 and Lys 32 do not experience any significant structural destabilization. It is also well established that desolvation penalties can destabilize electrostatic interactions at protein-protein interaction interfaces (43,44) and that the desolvation penalty of a cation-interaction is significantly less than that of a normal electrostatic interaction (45). Given the importance of Lys 32 as an anchoring interaction for huwentoxin-IV binding and activity, it is tempting to speculate that the role of the cation-interaction is to mitigate the energetic cost that would otherwise be associated with desolvation of Lys 32 and thus strengthen the overall equilibrium constant more in favor of binding (anchored by Lys 32 -Glu 811 according to our model).…”