Distinct roles of conventional non-covalent and cation–π interactions in protein stability

The different roles played by conventional non-covalent and cation–π interactions in stabilizing protein structures have been investigated using a dataset of 62 non-redundant DNA binding proteins. The stabilizing residues have been identified by a consensus approach using the concepts of hydrophobicity, long-range interactions and conservation of amino acid residues. The cation–π interactions have been delineated based on a geometric approach, such as, distance and energy criteria. I have identified 138 and 196 stabilizing residues, based on non-covalent and cation–π interactions, respectively. Interestingly, the stabilizing residues identified by consensus approach are not contributing to cation–π interactions. Further, 99% of the cation–π interactions forming residues are not identified as stabilizing ones. These results demonstrate that the roles of cation–π and non-covalent interactions are different from each other to the stability of protein structures. I have further evaluated the range of surrounding hydrophobicity, long-range order, stabilization center and conservation score for the residues that are contributing to cation–π interactions. The average surrounding hydrophobicity and long-range order of cation–π interaction forming residues are in the range of 7–15 kcal/mol and 0–0.03, respectively. I suggest that the inclusion of cation–π interaction along with conventional non-covalent interactions would provide deep insights for understanding the stability of protein structures.