Conformation and formation tendency of the cyclotetrapeptide cyclo(D-pro-D-pro-L-pro-L-pro): Experimental results and molecular modeling studies

✍ Scribed by Werner Mästle; Ulrich Link; Wolfgang Witschel; Ulf Thewalt; Thomas Weber; Manfred Rothe

• Publisher: Wiley (John Wiley & Sons)
• Year: 1991
• Tongue: English
• Weight: 787 KB
• Volume: 31
• Category: Article
• ISSN: 0006-3525
• DOI: 10.1002/bip.360310618

✦ Synopsis

The title compound represents the smallest member of cyclic proline peptides corresponding to the general formula c ( DDLL-Pro,), with a strictly D,D,L,L double-alternating sequence of the chiral amino acid residues. The cyclopeptides with n 2 2 could be synthesized from both DDLL-Pro4 ( 1 ) and DLLD-Pro, (2). The cyclic monomer ( n = 1 ) resulted only from 2 , whereas not even a trace could be found by cyclization of 1. The peptide exists in a strongly strained C, symmetrical conformation (x-ray analysis) with alternating cis and trans peptide bonds ( c tct form I ) . The cis peptide bonds deviate from planarity ( w = 22" ) ; two of the pyrrolidine rings show a "South" conformation (4 = -94' ) , whereas the other residues exhibit C,-endo puckering (4 = -124" ) . Two of the $ angles surprisingly occur at +41" (anti-cis') , the others are located in the trans' region. A quantitative ring opening occurs with trifluoroacetic acid at room temperature. In solution the existence of an isomeric ctcc sequence (form Ia) is indicated. Dreiding model studies also suggested a favorable conformation with a tctc sequence (form I1 ) . Consequently, we performed molecular mechanics calculations, based on the CHARMM force field and semiempirical quantum mechanical AM1 calculations (MOPAC program). Pronounced differences in the backbone parameters were found using these two methods. However, the theoretical studies evidenced the experimentally obtained differences in the cyclization tendencies of the linear precursors.