Asymmetric Contribution of Aromatic Interactions Stems from Spatial Positioning of the Interacting Aryl Pairs in β‐Hairpins

Isolated aromatic interactions in designed octapeptide β‐hairpin scaffolds display a near‐universal T‐shaped face‐to‐edge geometry in all positional permutations, with the exception of aryl‐Trp interactions. The heterogeneous asymmetric indole ring of Trp competes for a “shielding” face geometry, which lowers the scaffold stability in FtE aryl‐Trp pairs. Assessment of the contributions of aryl pairs (in the absence of solvent‐driven interactions) to the overall β‐hairpin structure reveals the superiority of Trp‐Phe and Trp‐Tyr contributions over the well‐established scaffold stabilization by Trp‐Trp.