Cyclic β-alanyl-β-alanine containing peptides: A new molecular tool for β-turned peptides

In the present paper we describe the synthesis, purification, and single-crystal x-ray analysis of the cyclic tetrapeptide cyclo-(L-Pro-L-Phe-β-Ala-β-Ala). This compound contains the β-alanyl-β-alanine dipeptide as putative cyclization arm to force the remaining dipeptide-L-Pro-L-Phe- in a β-turned conformation. Thepeptide was synthesized by classical methods and cyclization of the free linear tetrapeptide was accomplished in reasonable yields in diluted methylene chloride solution. The compound crystallizes in space group P21 from hot water with two independent tetrapeptide molecules and seven solvent molecules in the unit cell. This compound shows in the solid state an intramolecular hydrogen bond between the CO group of the β-Ala4 and the NH group of the β-Ala3 residues stabilizing a type I β-turn conformation in which Pro1 and Phe2 occupy the relative position 2 and 3 of the turn, respectively. A rather complex network of 18 hydrogen bonds involving all the remaining CO and NH groups and the water molecules is present in the crystal.