Empirical rules predicting conformation of cyclic tetrapeptides from primary structure

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Abstract
A useful set of empirical rules is put forward to predict the conformations of cyclic tetrapeptides and cyclic tetradepsipeptides on the basis of primary structure, briefly presented as follows: 1. A conformation allowing an intramolecular hydrogen bond (IMHB) of .gamma.-turn is preferred, and an ester bond always adopts a trans form. 2. On a right-handed peptide ring, the carbonyl group acylating a D residue is oriented to the upper side of the main ring. 3. The carbonyl group acylating a D proline or an N-methyl-D-amino acid residue is oriented to the lower side of the ring, forming a cis bond. 4. The LDDL configurational sequence adopts a cis-trans-cis-trans backbone with Ci symmetry. 5. A glycine residue behaves as a D residue in an L-peptide. Conformations of cyclotetrapeptides containing two glycine residues at diametric positions or containing an N-methyldehydroamino acid residue are predicted by these rules. Energetical rationalization of the rules and prediction of possible new conformations are described. Conformations of cyclo(-L-Pro-L-Leu-D-Tyr(Me)-L-Ile-) (1) and cyclo (-L-Pro-D-Leu-D-Tyr(Me)-L-Ile) (2) are compared. Results of n.m.r. experiments showed that compound 1 adopts a unique cis-trans-trans-trans backbone with a .gamma.-turn IMHB, and 2 has a cis-trans-cis-trans backbone with ci symmetry. These observations confirmed the rules described above. Peptides 1 and 2 are the first diastereomeric peptides with trans (LD) and cis (DD) secondary amide bonds.

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