Design of peptides with alpha,beta-dehydro-residues: synthesis, and crystal and molecular structure of 3(10)-helical tetrapeptide BOC-L-Val-Delta Phe-Delta Phe-L-Ile-OCH3

The peptide Boc-L-Val-Delta Phe-Delta Phe-L-Ile-OCH3 was synthesized using the azlactone method in the solution phase, and its crystal and molecular s tructures were determined by X-ray diffraction. Single crystals were grown by slow evaporation from solution in methanol at 25 degrees C. The crystals belong to an orthorhombic space group P2(1)2(1)2(1) with a = 22.882(7) Ang strom, b = 15.430(5) Angstrom, c = 18.330(5) Angstrom and Z = 4. The struct ure was determined by direct methods and refined by a least-squares procedu re to an R-value of 0.073. The peptide adopts a right-handed 3(10)-helical conformation with backbone torsion angles: phi(1) = 56.0(6)degrees, psi(1) = -38.0(6)degrees, phi(2) = -53.8(6)degrees, psi(2) = 23.6(6)degrees, phi(3 ) = -82.9(6)degrees, psi(3) = -10.6(7)degrees, phi(4) = 124.9(5)degrees. Al l the peptide bonds are trans. The conformation is stabilized by intramolec ular 4-->1 hydrogen bonds involving Boc carbonyl oxygen and NH of Delta Phe (3) and CO of Val(1) and NH of Ile(4). it is noteworthy that the two other chemically very similar peptides: Boc-Val-Delta Phe-Delta Phe-Ala-OCH3 (i) and Boc-Val-Delta Phe-Delta Phe-Val-OCH3 (ii) with differences only at the fourth position have been found to adopt folded conformations with two over lapping beta-turns of types II and III', respectively, whereas the present peptide adopts two overlapping beta-turns of type Ill. Thus the introductio n of lie at fourth position in a sequence Val-Delta Phe-Delta Phe-X results in the formation of a 3(10)-helix. The crystal structure is stabilized by intermolecular hydrogen bonds involving NH of Va(1) and carbonyl oxygen of a symmetry related (-x, y-1/2, 1/2 + z) Delta Phe(2) and NH of Delta Phe(2) with carbonyl oxygen of a symmetry related (x, y1/2, 1/2 + z) Ile(4). This gives rise to long columns of helical molecules linked head to tail runnin g along [010] direction.