Design of peptides with αβ‐dehydro residues: Synthesis, crystal structure and molecular conformation of N‐Boc‐L‐Ile‐ΔPhe‐L‐Trp‐OCH3

Abstract

The dehydro-peptide Boc-L-Ile-deltaPhe-L-Trp-OCH3 was synthesized by the azlactone method in the solution phase. The peptide was crystallized from methanol in an orthorhombic space group P2(1)2(1)2(1)with a = 10.777(2), b = 11.224(2), c = 26.627(10) A. The structure was determined by direct methods and refined to an R value of 0.069 for 3093 observed reflections [I > or = 2delta(I)]. The peptide failed to adopt a folded conformation with backbone torsion angles: phi1 = 90.8(8)degrees, psi1 = -151.6(6)degrees, phi2 = 89.0(8)degrees, psi2 = 15.9(9)degrees, phi3 = 165.7(7)degrees, psi3T = -166.0(7)degrees . A general rule derived from earlier studies indicates that a three-peptide unit sequence with a deltaPhe at the (i + 2) position adopts a beta-turn II conformation. Because the branched beta-carbon residues such as valine and isoleucine have strong conformational preferences, they combine with the deltaPhe residue differently to generate a unique set of conformations in such peptides. The presence of beta-branched residues simultaneously at both (i + 1) and (i + 3) positions induces unfolded conformations in tetrapeptides, but a beta-branched residue substituted only at (i + 3) position can not prevent the formation of a folded beta-turn II conformation. On the other hand, the present structure shows that a beta-branched residue substituted at the (i + 1) position prevents the formation of a beta-turn II conformation. These observations indicate that a beta-branched residue at the (i + 1) position prevents a folded conformation whereas it cannot generate the same degree of effect from the (i + 3) position. This may be because of the trans disposition of the planar deltaPhe side-chain with respect to the C=O group in the residue. The molecules are packed in an anti-parallel manner to generate N2-H2...O2 (-x, y -1/2, -z + 3/2) and N3epsilon1-H3epsilon1 ...O1(-X, y -1/2, -z + 3/2) hydrogen bonds.