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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.
Gallivan et al. (Fri,) studied this question.