BETA-ALANINE CONTAINING CYCLIC-PEPTIDES WITH PREDETERMINED TURNED STRUCTURE .5.

In the present paper we describe the synthesis, purification, single c rystal x-ray analysis, and solution structural characterization by nmr spectroscopy, combined with restrained molecular dynamic simulations, of the cyclic hexapeptide cyclo-(Pro-Phe-beta-Ala-Phe-Phe-beta-Ala). The peptide was synthesized by classical solution methods and the cycl ization of the free hexapeptide was accomplished in good yields in dil uted methylenechloride solution using N,N-dicyclohexyl-carbodiimide. T he compound crystallizes in the monoclinic space group P2(1) from meth anol/ethyl acetate. The molecule adopts in the solid state a conformat ion characterized by cis beta-Ala(6)-Pro(1) peptide bond. The alpha-am ino acid residues are at the corner positions of turned structures. Th e Pro(1)-Phe(2) segment is incorporated in a pseudo type I beta-turn, while Phe(4)-Phe(5) is in a typical type I beta-turn. Assignment of al l H-1 and C-13 resonances was achieved by homo- and heteronuclear two- dimensional techniques in dimethylsulfoxide (DMSO) solutions. The conf ormational analysis was based on interproton distances derived from ro tating frame nuclear Overhauser effect spectroscopy spectra and homonu clear coupling constants. Restrained molecular dynamic simulation in v acuo was also performed to built refined molecular models. The molecul e is present in DMSO solution as two slowly interconverting conformers , characterized by a cis-trans isomerism around the beta-Ala(6)-Pro(1) peptide bond, This work confirms our expectations on the low propensi ty of beta-alanyl residues to be positioned at the corners of turned s tructure. (C) 1994 John Wiley and Sons, Inc.