Beta-alanine containing cyclic peptides with turned structure: the "pseudo type II beta-turn." VI.

In the present paper we describe the synthesis, purification, single crystal x-ray analysis, and nmr solution characterization, combined with restrained molecular dynamic simulations, of the cyclic hexapeptide cyclo-(L-Pro-L-Phe-beta-Ala)2. The peptide was synthesized by classical solution methods and the cyclization of the free hexapeptide was accomplished in good yields in diluted methylene chloride solution using N,N-dicyclohexyl-carbodiimide. The compound crystallizes in the monoclinic space group P2(1) from methanol-dichloromethane solution. The two identical halves of the molecule adopt in the solid state two different conformations. One beta-Ala-L-Pro peptide bond is trans, while the second is cis. The molecule is present in dimethylsulfoxide d6 solutions as a mixture of conformational families. One of these corresponds to a C2 symmetrical molecule with both beta-Ala-Pro cis peptide bonds, while the second major conformation is very similar to that observed in the solid state. All Pro-Phe segments, both in the solid state and the symmetrical and unsymmetrical solution conformations, display phi, psi angles close to that of position i + 1 and i + 2 of type II beta-turns. In addition, the segments preceded by a trans beta-Ala-Pro peptide bond are characterized by a typical i<--i + 3 hydrogen bond, which is absent in the conformer containing a cis beta-Ala-Pro peptide bond. The latter conformation corresponds to a new structural domain we define as the "pseudo type II beta-turn."