Channel-forming, self-assembling, bishelical amphiphilic peptides: design, synthesis and crystal structure of Py(Aib_n)₂, n = 2, 3, 4

Abstract

The design, synthesis, characterization and self-assembling properties of a new class of amphiphilic peptides, constructed from a bifunctional polar core attached to totally hydrophobic arms, are presented. The first series of this class, represented by the general structure Py(Aib_n)₂ (Py = 2,6-pyridine dicarbonyl unit; Aib = α,α'-dimethyl glycine; n= 1–4), is prepared in a single step by the condensation of commercially available 2,6-pyridine dicarbonyl dichloride with the methyl ester of homo oligoAib peptide (Aib_n-OMe) in the presence of triethyl amine. ¹H NMR VT and ROESY studies indicated the presence of a common structural feature of 2-fold symmetry and an NH…N hydrogen bond for all the members. Whereas the Aib3 segment in Py(Aib₃)₂ showed only the onset of a 3₁₀-helical structure, the presence of a well-formed 3₁₀-helix in both Aib₄ arms of Py(Aib₄)₂ was evident in the ¹H NMR of the bispeptide. X-ray crystallographic studies have shown that in the solid state, whereas Py(Aib2)₂ molecules organize into a sheet-like structure and Py(Aib3)₂ molecules form a double-stranded string assembly, the tetra Aib bispeptide, Py(Aib4)₂, is organized to form a tetrameric assembly which in turn extends into a continuous channel-like structure. The channel is totally hydrophobic in the interior and can selectively encapsulate lipophilic ester (CH₃COOR, R = C₂H₅, C₅H₁₁) molecules, as shown by the crystal structures of the encapsulating channel. The crystal structure parameters are: 1b, Py(Aib2)₂, C₂₅H₃₇N₅O₈, sp. gr. P2₁2₁2₁, a = 9.170(1) Å, b = 16.215(2) Å, c = 20.091(3) Å, R = 4.80; 1c, Py(Aib3)₂, C₃₃H₅₁N₇O₁₀·H₂O, sp. gr. P, a = 11.040(1) Å, b = 12.367(1) Å, c = 16.959(1) Å,α α= 102.41°, β β= 97.29°, γγ= 110.83°, R1 = 6.94; 1 da, Py(Aib4)₂et ac, C₄₁H₆₅N₉O₁₂1.5H₂O·C₄H₈O₂, sp. gr. P, a = 16.064(4) Å, b = 16.156 Å, c = 21.655(5) Å, α= 90.14(1)°, β= 101.38(2)°, γ= 97.07(1)°, Z = 4, R₁ = 9.03;1db,Py(Aib4)₂amylac,C₄₁H₆₅N₉O₁₂H₂O ·C₇H₁₄O₂, P2₁/c, a = 16.890(1) Å, b = 17.523(1) Å, c = 20.411(1) Å, β= 98.18 °, Z = 4, R = 11.1 (with disorder).