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.