Peptides backbone flexibility

The influence of backbone flexibility was seen, for example, when the stability of the linear tetrapeptide 6.70 was compared to that of a cyclic hexa-peptide derivative of the same sequence [91]. Indeed, the cyclic peptide was approximately one order of magnitude more stable than the linear peptide in the pH range of 2-7. The results at higher pH values were inconclusive since the stability of the cyclic peptide decreased dramatically due to the degradation of a disulfide bond absent in the linear peptide. 

An important factor in the structure of protein-DNA complexes can be the peptide backbone. The amide bond can fimction as an H-bond acceptor as well an H-bond donor. Due to the reduced flexibility of the backbone vs. side chain (resonance stabilization of the peptide bond), H-bonds to the peptide backbone lead to a rigid and tight arrangement in the complex and contribute extensively to the exact fit between protein and nucleic acid. 

Novel properties of peptides can be obtained by incorporation of Saa. Peptides are characteristically highly flexible molecules whose 3D structure is strongly influenced by their environment. Their often unordered conformation in solution complicates their use in determining the receptor bound bioactive structure.182,831 Conformational constraints,184-881 cyclization/891 and/or replacement of the peptide backbone or parts of it162 90-921 can provide information on the required conformation for biological activity. 

Thus, the solid phase synthesis of a peptide library led to a diverse set of RabGGTase inhibitors with moderate inhibition of prenylation in cells. These results show that the flexible peptide backbone is probably not suitable for a structure-guided inhibitor approach or SAR analysis due to different binding modes adopted by the peptides. However, the structural insights obtained from the inhibitor-RabGGTase cocrystal structures provided crucial information that was used for the development of other potent and specific RabGGTase inhibitors. 

Cyclization is one of the earliest techniques applied to design peptidomimetics. Cyclic peptides are more stable to amide bond hydrolysis and allow less conformational flexibility consequently, the resulting analogs are anticipated to be more selective and less toxic. Methods for restricting conformations include peptide backbone cyclization, disulfide bond formation, side-chain cyclization, and metal ion chelation. 

Although the cyclic structure restricts the conformation of the peptide backbone, there is still considerable conformational flexibility around the Tyr and Phe side chains... 

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