Design of peptides: synthesis, crystal structure and molecular conformation of N-Boc-_L -Val-ΔPhe-_L -Val-OC H₃

Abstract

The dehydropeptide Boc-_L -Val-ΔPhe-_L -Val-OC H₃ was synthesized by azlactone method in solution phase. The peptide crystallized from its solution in a methanol/water mixture (70:30) in space group P2₁2₁2₁ with a= 13.638(1)Å, B = 22.864(3)Å, C = 27.600(2)Å, V= 8606(1)Å ³. The structure was determined by direct methods and refined to an R value of 0.089 for 3326 observed (1 ≥ 2β(1)) reflections. The structure contains three crystallographically independent molecules. Two molecules (A and B) adopt identical conformations with φ₁(A)=-130(1), φ₁(B)=-139(1), ψ₁(A)= 153(1), ψ₁(B)= 145(1), φ₂(A) = 62(1), φ₂(B)= 56(1), ψ₂(A)= 33(1), ψ₂(B)= 33(1), φ₃(A)=-75(1), φ₃(B)=-77(1) ψ₃^T(A)= 152(1) and ψ₃^T(B)= 163(1)°. The conformation of the third molecule (C) is different as in that torsion angle ψ₁ is rotated by 180°. The backbone torsion angles are φ₁=-128(2), ψ₁= -37(2), φ₂ = 65(1), ψ₂ = 35(1), φ₃= -84(1) and ψ₃^T= 169(1). It is significant that a characteristic β-turn II conformation as observed in peptides with a ΔPhe residue at (i+2) position has not been observed in this case. Thus the present structure demonstrates that an (i+2) substituted ΔPhe with branched β-carbon residue Val on both sides of it in a three peptide unit sequence does not adopt a folded conformation. The three independent molecules in the asymmetric unit form three hydrogen bonds between each pair of molecules and generates a tightly interacting unit of three molecules. These units pack into the crystalline state with hydrogen bonds involving N₁, N₂ and N₃ of molecule C and O₁' and O₂' of symmetry related molecule A. The structure confirms that a peptide containing a ΔPhe residue at (i+2) position with branched β-carbon residues as its immediate neighbours on both sides does not adopt a folded conformation. This structure further demonstrates that the unfolded structures without any intramolecular hydrogen bond can be influenced by intermolecular forces, thus causing conformational variations in saturated residues. It is noteworthy that the conformation of the ΔPhe residue remains unchanged in all the three molecules.