Hexapeptide, cyclic, conformation

Pan CP, Callis PR, Barkley MD (2006) Dependence of tryptophan emission wavelength on conformation in cyclic hexapeptides. J Phys Chem B 110(13) 7009-7016... 

Design of Novel Cyclic Hexapeptide Somatostatin Analogs from a Model of the Bioactive Conformation... 

Different ring sizes exhibit distinct characteristics, especially in the case of smaller cyclic peptides (di- to hexapeptides), including ring-closing reactions, which will be treated briefly, and related conformational characteristics. 

Cyclic hexapeptides can be considered as the classical and the most prominent representatives among cyclic peptides. Natural products are numerous and widespread (see Scheme 11), e.g. segetalin A,[278] bouvardin/279280 RA-IIlJ281-283 or pneumocandin B0,[284 286] and this type of ring structure has frequently been used to stabilize conformational preferences of bioactive portions of larger peptides or even proteins. 

The conformational properties of cyclic hexapeptides have been extensively investigated over decades by the use of suitable model systems.1137-288 With appropriate peptide sequences the phenomena of cycloenantiomerism and cyclodiastereomerism have been defined 289,290 and reverse turns have been classified for model ring structures. 206 Similarly, the retro-inverso concept was established for the first time with cyclic hexapeptides 130 in this context it is noteworthy that the total retro-inverso structure of a cyclic peptide is especially easy to synthesize, as it does not require specific building blocks but only inverted chirality and full-sequence reversal. 265 ... 

The cyclic hexapeptide c(-Pro-Gly-)3 has been extensively investigated. 181 184 CD, NMR, and molecular mechanics indicate a C3-symmetric conformation with three inverse y-turns in nonpolar solvents. In polar solvents, a nonsymmetrical conformation is dominant, but in the presence of divalent cations, 1 1 and 2 1 complexes with C3 symmetry are formed. 

The steric bulk of the thioamide sulfur results in conformational changes that have been documented in cyclopentapeptide and cyclohexapeptide model systems (for more details see Vol. E22b, Section 6.8.5.2.1). For example, in c[-Proi(>[C(=S)-NH]Gly-Pro-Gly-D-Phe-], the first synthetic cyclic thiopeptide, an intramolecular y-turn seen in the all-amide parent compound by NMR methods was perturbed by the putative interaction of sulfur with the adjacent Pro s (3-protons.[9 On the other hand, in a cyclic hexapeptide, the enhanced H-bond donor capacity of the thioamide NH led to the formation of a relatively strong intramolecular H-bond stabilized (3-turn, which was frame shifted compared to that found in its all-amide parent peptide. 10 ... 

We have been more concerned with the nature of the water around proteins and peptides. To this end we have investigated the structure and energetics of the solvent, both ordered and disordered around the enzyme lysozyme, in the triclinic crystal[l7d]. In addition to lysozyme, we have characterized the water structure and fluctuations in the crystal of a cyclic hexapeptide, (L-Ala-L-Pro-D-Phe)9[20]. and studied the effect of solvent on the conformation of the dipeptide of alanine[2l] and on the equilibria between extended and helical alanine polypeptides such as those discussed in the previous section[22]. The latter systems simulate aqueous solution conditions rather than crystalline environment. 

Figure 38 Representation of the equilibrium between the cyclic and acyclic forms of a hexapeptide. The N- and C-terminal blocking groups, CH3CO— and —NHCH3, respectively, are not shown.233 The standard free energy change for this process depends on the intrinsic chemistry to form a disulfide bond from two sulfhydryl groups, the tendency of Pro-Giy (or any other dipeptide in this position) to form a P turn, and the tendencies of residues X and Y to adopt the extended conformation (and interact with each other). Table 5 of Reference 234 illustrates the range of standard free energy changes for a family of such hexapeptides.

P. J. Milburn, Y. Konishi, Y. C. Meinwald, and H. A. Scheraga, J. Am. Chem. Soc., 109, 4486 (1987). Erratum ibid., 109, 8123 (1987). Chain Reversals in Model Peptides Studies of Cystine-Containing Cyclic Peptides. I. Conformational Free Energies of Cyclization of Hexapeptides of Sequence Ac-Cys-X-Pro-Gly-Y-Cys-NHMe. 

Cyclic peptides containing glutamic acid or aspartic acid are useful for investigating the effect of the side chains, which can be modified by esterification, on the main-chain conformation. However, few cyclic peptides containing acidic amino acid residues have been synthesized. The present author has synthesized a series of cyclic hexapeptides Cyclo-(Gly-X-Gly)2 where X = Glu(OBzl), Glu(OMe), Glu, Asp (OBzl), and Asp, and investigated their solution conformations using NMR spectroscopy 113). 

Cyclic hexapeptides containing sarcosine residues are considered to be fairly flexible, in view of the nature of the N-CH3 peptide bond(70, US) and the ring number. The present author has synthesized a series of cyclic hexapeptides containing sarcosine residues, and investigated the relationriiip between the conformational multiplicity as studied by NMR spectroscopy and the nature of constitutive amino acid residues. 

Finally, the conformation of Cyclo-(Pro-Gly-Gly)2, where two sarcosine residues of Cyclo- Sar-Gly-Gly)2 were replaced by proline residues, was analyzed. This cyclic hexapeptide has been investigated by Schwyzer etaL (25,117.120) and Pease et al. (116) and was shown to take a C2-tymmetric conformation with two Gly-NH protons intramolecularly hydrogen-bonded. Schwyzer et aL (117,120) and Pease etal. (116) investigated and NMR spectra of Cydo-(Pro-(3y-(3y)2 and... 

The above invest tions and considerations revealed that the ionic denaturant-cyclic peptide interactions in DMSO manifested themselves as the conformational charge of the cydic peptide through the interactions between ions (possibly anions) produced from the added salts and the peptide bond. If the large downfield shift is always observed for the internal peptide NH protons vdien Gu HCl is added to a DMSO solution of cyclic hexapeptide, the downfield shift can be used as a criterion for the peptide proton beijig internal. 

Conformational properties of a series of cyclic hexapeptides containing sarcosine have been described in Section 3.8.2. The interactions of these cyclic hexapeptides with metal salts will now be discussed in connection with their conformational properties (ii 9). 

---