Peptides conformational behavior

Chirooptical properties give more subtle information on the conformational behavior of biopolymers and peptides in solution. In early experiments, optical rotation and optical rotatory dispersion (ORD) have been recognized as valuable techniques, followed more recently by significant progress and refinements in the equipment which have resulted in the routine measurements of applied circular dichroism (CD). 

The characteristic properties of peptides result from the presence of a chain of several or many amide bonds. A first problem is that of numbering, and here Fig. 6.1 taken from the IUPAC-IUB rules may help. A second and major aspect of the structure of peptides is their conformational behavior. Three torsion angles exist in the backbone (Fig. 6.2). The dihedral angle co (omega) describes rotation about C-N,

rotation about N-C , and ip (psi) describes rotation about C -C. Fig. 6.2 represents a peptide in a fully extended conformation where these angles have a value of 180°. 

Increased occurrence of d.v-peptide bonds and differences in conformational behavior ... 

Cyclic peptides have been synthesized not only for the purpose of improving biological activities and selectivity, but also to explore basic features of secondary structures in peptides and to investigate with such mimetic compounds the conformational behavior of proteins. For this purpose artificial building blocks have been frequently used or amide bonds have been modified isosterically. Nature also offers a variety of modifications in cyclic peptides that are critically involved in their bioactivity. Some of the most common natural and synthetic modifications including unusual structural elements such as thiazoles (and dihy-drothiazoles) and oxazoles (and dihydrooxazoles) with broad synthetic applications will be presented in the following section. 

Hopkins et al. described the synthesis of a series of amino acids 107-110 bearing one half of EDTA, an aminodiacetic acid group, on the side chain (Scheme 32)J70 71 Two of these amino acids were incorporated at different positions in several peptide structures and their conformational behavior was studied in the presence of metal ions. In most cases, the side-chain complexation of Cd2+ or Cu2+ leads to an increase of helicity demonstrating the involvement of the two distant ligand side chains. In the case of peptide 111, addition of Cd2+ changed the helical content from approximately 0 to 82%. 

Fletcher, M. D., Campbell, M. M. Partially Modified Retro-Inverso Peptides Development, Synthesis, and Conformational Behavior. Chem. Rev. 1998, 98, 763-796. 

C. Adamo, V. Dillet and V. Barone, Solvent effects on the conformational behavior of model peptides. A comparison between different continuum models, Chem. Phys. Lett., 263 (1996) 113. 

Several natural products, for example siderophores, contain the N-hydroxy amide Y[CON(OH)] motif [138], Within a peptide backbone, this group increases the stability to enzyme degradation and induces characteristic conformational behavior [139]. In addition to the synthesis in solution of N-hydroxy amide-containing peptides (which is not trivial), a new solid-phase approach has recently been developed [140]. To explore the features of the N-hydroxy amide moiety using automated and combinatorial techniques, a method for the preparation of v /[CON(OH)] peptide ligands for MHC-I molecules has been elaborated [140], The strategy for the parallel preparation of these peptidomimetics on a solid support is illustrated in Scheme 7.9. The key step is the nucleophilic substitution reaction of resin-bound bromocarboxylic acids by O-benzylhydroxylamine, which requires several days. 

Additionally, a set of tripeptide sequences was extracted from the PDB and analyzed to derive torsion histograms describing the conformational preferences of peptidic portions in ligands. Implicitly, these histograms contain the information about the conformational behavior of molecules in a structured molecular environment with varying intermolecular directional forces and dielectric conditions in the... 

As the term polyelectrolyte can also be extended to encompass natural biopolymers, which contain ionizable groups such as peptides, proteins, and DNA, it is perhaps not surprising that synthetic polyelectrolytes are often used as simple models for more complex biological systems. Indeed, many of the photophyscial techniques discussed in this chapter were developed by biologists and biophysicists interested in the conformational behavior and interactions of biopolymers [1]. 

J. S. Perkyns, Y. Wang, and M. Pettitt,/. Am. Chem. Soc., 118,1164 (1996). Salting in Peptides Conformationally Dependent Solubilities and Phase Behavior of a Tripeptide Zwitter-ion in Electrolyte Solution. 

Altman, M., Lee, P., Rich, A., Zhang, S. Conformational behavior of ionic self-complementary peptides. Protein Sci. 9,1095-1105 (2000)... 

Perkyns, J. S., Y. Wang, and B. M. Pettitt. 1996. Salting in peptides Conformationally dependent solubilities and phase behavior of a tripeptide zwitterion in electrolyte solution. Journal of the American Chemical Society. 118, 1164. 

Both Pro and Gly have to be considered unusual among the 20 naturally occurring a-amino acids. Their significant influence on the conformation of a host peptide could a priori be expected from a look at the conformational energy maps (Rama-chandran maps) of fiiese two residues. To make it possible to extoid the host-guest principle to amino acids with less dramatic conformational behavior, the original approach was modified such as to insert two vicinal guest residues into the host sequence. 

The correlations between physico-chemical properties and peptide conformation described in this chapter give in principle M ess to an indirect route for the prediction of the physico-chemical behavior of peptides from thdr primary structure ... 

Any time there is a conformation other than a random coil present on binding to the sorbent, it might be expected that deviations from predicted retention times would result. However, Zhou et al. [200] clearly established that, in the absence of a preferred binding domain such as the hydrophobic face of an amphipathic a-helix, the a-helical conformation of a peptide does not have any significant effect on peptide retention behavior in RPC. Thus, if the hydrophobic residues of a peptide are well distributed around the a-helical structure of the peptide, all residues in the a-helix are contributing to the overall hydrophobicity... 

DCR has also been used to prepare amino acid and dipeptide mimetics. The synthesis of Pro-Gly and Pro-Xaa dipeptide mimetics (9 and 10, respectively, where Xaa is an unspecified amino acid) was reported by Gmeiner et al. and the triazolyldipeptides were assembled using a 1,3-dipolar cycloaddition (thermal or Cu -catalyzed) to provide 1,4-and 1,5-substituted tiiazoles (see Figure 10.2). The conformational behavior of the resulting peptides was analyzed by NMR and FTIR and the results suggested that the cis/ trans ratios could be tuned by the triazole and its substitution. 

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