Stereochemical studies of cyclic peptides.

Conformational variety in cyclic tripeptides was examined using a combination of stereochemical and energy minimization methods. Four different conformations were found possible: (i) a threefold symmetrical one with all peptide units in cis configuration, with very little nonplanarity; (ii) an asymmetrical one with all cis units and with a larger nonplanarity (ccc); and (iii) two possible conformations with two cis and one trans peptide unit, (cct)₁ and (cct)₂. All these conformations can accommodate both sarcosyl and prolyl residues, which are known to occur in cis peptide units. The symmetric and the (cct)₂ conformations can accommodate only a homo-isomeric sequence of prolyl residues, and the other two asymmetric conformations (ccc) and (cct)₁ can accommodate hetero-isomeric sequence of Pro. In order to relieve some severe steric hindrances cis peptide units show a need-based flexibility in the peptide bond angles. All the four conformations are known to occur in solid state as well and the results obtained compare reasonably well with the available crystal structure information.     

Conformational studies on model dipeptides of Gly,L -Ala and their Cα-substituted analogs

As a part of the development of conformational guidelines for the design of metabolically altered peptidomimetics, we present conformational energy calculations on model dipeptide compounds with glycine (Gly), L-alanine (Ala), α-aminoisobutyric acid (Aib), L-tert-butylglycine (Tle), L-phenylglycine (Phg), (α,α)-diphenylglycine (Dφg), L-2-aminobutyric acid (Abu), 2-amino-2-ethylbutync acid (Deg), L-2-amino-2-vinylacetic acid (Ava) and (α,α)-divinylglycine (Dvg). The energy calculations have been made using molecular mechanics methods with a force field derived from MM2. The salient features are expressed in terms of conformational energy plots, drawn as a function of the backbone torsion angles φ(C_i-1′-N_i-C_i^α-C_i′) and ψ(N_i- C_i^α-N_{i + 1}). The low-energy structures of these compounds are qualitatively consistent with the X-ray crystal structure analyses of peptides and peptidomimetics. They are also in agreement with the results of the solution-phase studies carried out by NMR and IR techniques. The results obtained have important implications in the design of conformationally restricted peptidomimetics.