Design of peptides using α,β-dehydro-residues: synthesis, crystal structure and molecular conformation of N-Boc-L-Val-ΔPhe-ΔPhe-L-Ala-OCH₃

Abstract

To obtain general rules of peptide design using α,β-dehydro-residues, a sequence with two consecutive ΔPhe-residues, Boc-L-Val-ΔPhe-ΔPhe- L-Ala-OCH₃, was synthesized by azlactone method in solution phase. The peptide was crystallized from its solution in an acetone/water mixture (70:30) in space group P6₁ with a=b=14.912(3) Å, c= 25.548(5) Å, V=4912.0(6) ų. The structure was determined by direct methods and refined by a full matrix least-squares procedure to an R value of 0.079 for 2891 observed [I∃3σ(I)] reflections. The backbone torsion angles φ₁=-54(1)°, ψ₁= 129(1)°, ω₁=-177(1)°, φ₂ =57(1)°, ψ₂=15(1)°, ω₂ =-170(1)°, φ₃=80(1)°, ψ₃ =7(2)°, ω₃=-177(1)°, φ₄ =-108(1)° and ψ^T₄=-34 (1)° suggest that the peptide adopts a folded conformation with two overlapping β-turns of types II and III'. These turns are stabilized by two intramolecular hydrogen bonds between the CO of the Boc group and the NH of ΔPhe³ and the CO of Val¹ and the NH of Ala⁴. The torsion angles of ΔPhe² and ΔPhe³ side chains are similar and indicate that the two ΔPhe residues are essentiallyplanar. The folded molecules form head-to- tail intermolecular hydrogen bonds giving rise to continuous helical columns which run parallel to the c-axis. This structure established the formation of two β-turns of types II and III' respectively for sequences containing two consecutive ΔPhe residues at (i+2) and (i+3) positions with a branched β-carbon residue at one end of the tetrapeptide.