DESIGN OF PEPTIDES WITH ALPHA,BETA-DEHYDRO RESIDUES - SYNTHESIS, CRYSTAL-STRUCTURE AND MOLECULAR-CONFORMATION OF N-BOC-L-ILE-DELTA-PHE-L-TRP-OCH3

The dehydre-peptide Boc-L-Ile-Delta Phe-L-Trp-OCH3 was synthesized by the azlactone method in the solution phase. The peptide was crystalliz ed 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) Angstrom. The structure was determined by direct methods and refined to an R value of 0.069 for 30 93 observed reflections [l greater than or equal to 2 sigma(l)]. The p eptide failed to adopt a folded conformation with backbone torsion ang les: phi(1) = 90.8(8)degrees, psi(1) = -151.6(6)degrees phi(2) = 89.0( 8)degrees, psi(2) = 15.9(9)degrees, phi(3) = 165.7(7)degrees, psi(3)(T ) = -166.0(7)degrees. A general rule derived from earlier studies indi cates that a three-peptide unit sequence with a Delta Phe at the (i 2) position adopts a beta-turn II conformation. Because the branched b eta-carbon residues such as valine and isoleucine have strong conforma tional preferences, they combine with the Delta Phe residue differentl y to generate a unique set of conformations in such peptides. The pres ence of beta-branched residues simultaneously at both (i + i) and (i 3) positions induces unfolded conformations in tetrapeptides, but a b eta-branched residue substituted only at (i + 3) position can not prev ent the formation of a folded beta-turn II conformation. On the other hand, the present structure shows that a beta-branched residue substit uted 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 + i) position prevents a folded conformation whereas it can not generate the same degree of effect from the (i + 3) position. This may be because of the trans disposition of the planar Delta Phe side- chain with respect to the C=O group in the residue. The molecules are packed in an anti-parallel manner to generate N-2-H-2...O-2 (-x, y -1/ 2, -z + 3/2) and N-3(epsilon 1)-H-3(epsilon 1) ...O-1(-x, y -1/2, -z 3/2) hydrogen bonds.