Design of peptides: Synthesis, crystal structure and molecular conformation of N-Boc-L-Val-Delta Phe-L-Val-OC H-3

The dehydropeptide Boc-L-Val-Delta Phe-L-Val-OC H-3 was synthesized by azlactone method in solution phase. The peptide crystallized from its solution in a methanol/water mixture (70:30) in space group P2(1)2(1)2(1) with a=13.638(1)Angstrom, b=22.864(3)Angstrom, c=27.600(2)Angstrom, V=8606(1)Angstrom(3). The structure was determined by direct methods and refined to an R value of 0.089 for 3326 observed {1 greater than or equal to 2 sigma(I)} reflections. The structure contains three crystallographically independent molecules. Two molecules (A and B) adopt identical conformations with phi(1)(A)=-130(1), phi(1)(B)=-139(1), psi(1)(A)=153(1), psi(1)(B)=145(1), phi(2)(A)=62(1), phi(2)(B)=56(1), psi(2)(A)=33(1), phi(2)(B)=33(1), phi(3)(A)=-75(1), phi(3)(B)=-77(1) psi(3)(T)(A)=152(1) and psi(3)(T)(B)=163(1)degrees. The conformation of the third molecule (C) is different as in that torsion angle psi(1) is rotated by 180 degrees. The backbone torsion angles are phi(1)=-128(2), psi(1)=-37(2), phi(2)=65(1), psi(2)=35(1), phi(3)=-84(1) and psi(3)(T)=169(1). It is significant that a characteristic beta-turn II conformation as observed in peptides with a Delta Phe residue at (i+2) position has not been observed in this case. Thus the present structure demonstrates that an (i+2) substituted Delta Phe with branched beta-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 N-1, N-2 and N-3 of molecule C and O-1' and O-2' of symmetry related molecule A. The structure confirms that a peptide containing a Delta Phe residue at (i+2) position with branched beta-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 Delta Phe residue remains unchanged in all the three molecules.