Both the native and non-native, constructed CH-p stacking interactions formed with tyrosine have comparable energetics to those involving phenylalanine, indicating that the effect of the neutral alcohol group on the overall interaction energy is minimal when evaluating CHp stacking interactions (Figure ). However, when the phenol group of tyrosine is fully deprotonated (pKa 10.1) or hydrogen bonded to negatively charged amino acids, the increased electron density in the aromatic ring could lead to stronger CH-p interactions. To examine the potential impact of increased electron density on CH-p stacking interaction strength, we converted the 51 native tyrosine CH-p stacking interactions to phenoxide CH-p stacking interactions by deprotonating the acidic hydrogen and coordinating an explicit water molecule to the charged oxygen atom for charge stabilization (see Computational Methods and Supporting Information Figure ). The resulting energetics indicate that phenoxide can form more stable CH-p stacking interactions than neutral tyrosine by 1.1 kcal/mol. This value was calculated at the low dielectric conditions (e=10) representative of a buried binding pocket, and the enhancement is more limited effect in the high dielectric conditions (e=80) representative of exposure to aqueous solution (Figure and Supporting Information Figure ). Thus, increasing the electron density in aromatic ring systems can stabilize CH-p stacking interactions, demonstrating the importance of the electrostatic contribution. These observations provide some rationale for the increased propensity of tyrosine, but not phenylalanine, in glycan binding sites and may enable rational design of more favorable protein-carbohydrate binding interactions in therapeutic efforts.