We explore optimal orientations, by examining examples of galactose-tryptophan CHp stacking interactions formed by three proteins, Bacteroides thetaiotaomicron glycoside hydrolase (BtGH97, PDB ID 5E1Q ), an Escherichia coli heat-labile enterotoxin (PDB ID 2XRS ), and Marasimus oreades agglutinin (MOA) an M. oreades lectin (PDB ID 3EF2 78 ). All three CH-p stacking interactions determined from the carbohydrate-amino acid pair from these proteins have highly favorable interaction energies. The B3LYP-D3 interaction energy of the CHp stacking interaction formed by BtGH97 is -8.3 kcal/mol, that of the enterotoxin is -9.6 kcal/mol, and that of the MOA lectin is -9.4 kcal/mol. Each protein-carbohydrate interaction has a distinct orientation and value along the dC1-Ctr + dC2-Ctr and dC4-Ctr + dC6-Ctr landscape (Figure ). BtGH97 forms CH-p component interactions with carbon atoms C1, C3, and C5, while the enterotoxin and MOA lectin form component interactions with carbon atoms C3, C4, C5, and C6, each at a unique interaction angle (Figure ). These differences in the CH-p stacking orientation enable each carbohydrate ligand to form optimal hydrogen bonds to neighboring amino acid residues while maintaining a favorable carbohydrate-aromatic stabilization (Figure and Supporting Information Figures ). Next, comparing the CH-p stacking interactions formed by each of the different amino acids, we observe that while the lowest-energy stacking interactions formed by tyrosine and phenylalanine occupy overlapping regions of the conformational space as those formed by tryptophan, the galactose-tryptophan interactions tend to have shorter values for dC1-Ctr + dC2-Ctr and dC4-Ctr + dC6-Ctr than tyrosine and phenylalanine interactions, with minima at 7.7 Å and 6.9 Å versus 8.1 Å and 7.6 Å, respectively (Figure ). This indicates that the same minimization of dC1-Ctr + dC2-Ctr and dC4-Ctr + dC6-Ctr possible for the bicyclic indole on tryptophan is not possible for smaller, unicyclic aromatic rings on tyrosine and phenylalanine and confirms that the size of the aromatic ring system is the driving factor that enables tryptophan to make stronger interactions.