Conformational and coordination properties of a peptide containing the novel α,α-bis(2-pyridyl)glycine amino acid

Abstract

A fully protected tripeptide containing a novel C^α,α-disubstituted glycine—α,α-di(2-pyridyl)glycine (2Dpy)—in the central position and C^α,α-dimethylglycine (Aib) in positions 1 and 3 was synthesized and structurally characterized by single crystal X-ray analysis. The 2Dpy residue bears two 2-pyridyl moieties, which may coordinate metal ions, and promote self-assembly of peptide units. The tripeptide Z-Aib¹-2Dpy²-Aib³-OCH₃ (Z: benzyloxycarbonyl) adopts in the solid state a folded type III (III′) β-turn conformation (with Aib¹-2Dpy² as corner residues), stabilized by an i ← i + 3 hydrogen bond between the Aib³ NH and the urethane CO group. The peptide was able to self-assemble in the presence of Cu(II) ions, giving rise to an octahedral complex with a 2 : 1 peptide/Cu(II) stoichiometry, which has been structurally characterized. The metal ion, arranged on a crystallographic symmetry centre, is coordinated by two symmetry related 2Dpy residues, which act as tridentate ligands: each 2Dpy residue donates to the Cu(II) the N atoms of both pyridyl moieties in the equatorial positions, and the carbonyl oxygen atom in the axial positions. A very similar folded conformation characterizes the peptide in both the free and metal-bound states. This indicates that the overall peptide structure is ready to coordinate the metal ion without substantial conformational changes. Metal binding of the tri-peptide toward copper ions was analyzed by UV-visible spectroscopy performed in methanol solution. The experimental data agree with an equilibrium between two species in solution, one in the ratio Cu/peptide 1 : 1, the other 1 : 2. The formation constants are 9.7 × 10³ M⁻¹ and 3.5 × 10² M⁻¹, respectively. The molar extinction coefficients are 66 ± 3 M⁻¹ cm⁻¹ (590 nm) for the 2 : 1 complex and 17 ± 2 M⁻¹ cm⁻¹ (690 nm) for the other. All the data obtained in the present work suggest that the 2Dpy residue is well suited to be accommodated into folded conformations. The spontaneous formation of an ordered structure by the 2Dpy containing tri-peptide and copper ions may guide toward the design of more elaborate self-assembling systems.