Design of peptides using alpha, beta-dehydro-residues: synthesis, crystal structure and molecular conformation of N-Boc-L-Val-delta Phe-delta Phe-L-Ala-OCH3.

To obtain general rules of peptide design using alpha, beta-dehydro-residues, a sequence with two consecutive delta Phe-residues, Boc-L-Val-delta Phe-delta Phe-L-Ala-OCH3, was synthesized by azlactone method in solution phase. The peptide was crystallized form its solution in an acetone/water mixture (70:30) in space group P6(1) with a = b = 14.912(3) A, c = 25.548(5) A, V = 4912.0(6) A3. 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 > or = 3 delta (1)] reflections. The backbone torsion angles phi 1 = 54(1) degrees, psi 1 = 129(1) degrees, omega 1 = -177(1) degrees, phi 2 = 57(1) degrees, psi 2 = 15(1) degrees, omega 2 = -170(1) degrees, phi 3 = 80(1) degrees, psi 3 = 7(2) degrees, omega 3 = -177(1) degrees, phi 4 = -108(1) degrees and psi T4 = -34(1) degrees suggest that the peptide adopts a folded conformation with two overlapping beta-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 delta Phe3 and the CO of Val1 and the NH of Ala4. The torsion angles of delta Phe2 and delta Phe3 side chains are similar and indicate that the two delta Phe residues are essentially planar. The folded molecules from 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 beta-turns of types II and III' respectively for sequences containing two consecutive delta Phe residues at (i + 2) and (i + 3) positions with a branched beta-carbon residue at one end of the tetrapeptide.