Aromatic interactions in tryptophan-containing peptides: crystal structures of model tryptophan peptides and phenylalanine analogs

Abstract

The crystal structures of the peptides, Boc-Leu-Trp-Val-OMe (1), Ac-Leu-Trp-Val-OMe (2a and 2b), Boc-Leu-Phe-Val-OMe (3), Ac-Leu-Phe-Val-OMe (4), and Boc-Ala-Aib-Leu-Trp-Val-OMe (5) have been determined by X-ray diffraction in order to explore the nature of interactions between aromatic rings, specifically the indole side chain of Trp residues. Peptide 1 adopts a type I β-turn conformation stabilized by an intramolecular 4→1 hydrogen bond. Molecules of 1 pack into helical columns stabilized by two intermolecular hydrogen bonds, Leu(1)NH...O(2)Trp(2) and IndoleNH...O(1)Leu(1). The superhelical columns further pack into the tetragonal space group P4₃ by means of a continuous network of indole-indole interactions. Peptide 2 crystallizes in two polymorphic forms, P2₁ (2a) and P2₁2₁2₁ (2b). In both forms, the peptide backbone is extended, with antiparallel β-sheet association being observed in crystals. Extended strand conformations and antiparallel β-sheet formation are also observed in the Phe-containing analogs, Boc-Leu-Phe-Val-OMe (3) and Ac-Leu-Phe-Val-OMe (4). Peptide 5 forms a short stretch of 3₁₀-helix. Analysis of aromatic-aromatic and aromatic-amide interactions in the structures of peptides, 1, 2a, 2b are reported along with the examples of 14 Trp-containing peptides from the Cambridge Crystallographic Database. The results suggest that there is no dramatic preference for a preferred orientation of two proximal indole rings. In Trp-containing peptides specific orientations of the indole ring, with respect to the preceding and succeeding peptide units, appear to be preferred in β-turns and extended structures.