Conformations of peptides

X-ray data suggest that the peptide linkage is planar in either small molecules or proteins themselves215-220. The planarity of the peptide linkage results into interesting structural patterns encountered in polypeptide molecules. Two important conformations of peptides are the a-helix and fully extended conformations221. Examination of the fully extended form of a polypeptide immediately reveals that this conformation enjoys considerable stabilization from the factors we have been discussing. 

I. L. Karie, X-ray Analysis Conformation of Peptides in the Crystalline State. In The Peptides. Analysis, Synthesis,... 

One strategy to control folding is to direct folds by introduction of S-hairpins, turns which are often associated with Pro incorporation in a polypeptide sequence. Constrained turn mimics have previously been employed in investigations of the active conformation of peptides. Clearly, from the above discussion of CyP and... 

Conformational analysis can be performed using a variety of methods.1161 Most important are X-ray analysis and NMR spectroscopic techniques, which allow detailed insights into the topology of the peptides. NMR combined with molecular dynamic calculations provides the spatial structure of the peptide, but also its dynamics in solution.13643491 Additional information can be obtained from FTIR,15,4521 CD,151,53-551 or Raman spectroscopy. 56,571 The results derived from such conformational analysis of cyclic peptides have a considerable impact on the study of the bioactive conformations of peptides and on the design of cyclic peptides as proteinomimetics.124,58,59,6301... 

Hopkins and co-workers [6] have used the selective complexation of transition metals by two distant EDTA modified amino acids to stabilize the a-helical conformation of peptides 2 and 3 (Fig. 3). The results were particularly impressive in the case of 3 where the helicity increased from 0 to about 80% upon complexation of Cd2 4 ions. Along the same lines, Ghadiri and coworkers [7] reported the important stabilization of the helical conformation of 4 and 5 by the formation of selective metal complexes (Ru2+, Zn2+, Cu2+, and Cd2+) involving either two imidazoles of histidines or one imidazole and one thiol from a cysteine separated by three amino acids (I, 1 + 4) (Fig. 4). They also reported that peptide 4 is Cd2+-selective and that the helical conformation of the inert Ru2+ complex of 5 is remarkably stable. For instance, it has a melting point 25 °C higher than the uncomplexed peptide in water. 

Fig. 7. Schematic representations of the a-helix (axial view) and the /J-sheet (side view) conformations of peptides 8-10 (CE = crown-ether side chain). (Reproduced with the permission of Ref, 10a)...

In this paper, we aim to elucidate the correlation between the chemical shift tensors and the conformation of peptides, by carrying out NMR shielding calculations using the ab initio GIAO-CHF MO with 6-31G basis set, in order to understand the 13C chemical shift and chemical shift tensor behavior of the peptides and polypeptides. 

At the time the work on the alanine tripeptide was published, it was considered nearly an act of heresy to postulate a solution structure for peptides with less than 25 amino acids. This was because techniques for monitoring solution conformation of peptides of this size often were unable to detect a preferred structure, and consequently, the notion developed that small peptides had no solution structure. In this work, we postulated that peptides as small as a tripeptide may exist in a set of preferred structures on the time scale of molecular vibrational transitions. This contention has been further confirmed by us via VCD studies on other alanine peptides, and by the VCD results on small proline-containing peptides [39,47], and more recently by NMR studies [4]. These results will be discussed next. 

A polypeptide chain assumes the a-helical conformation because this is where H bonds can be formed most effectively. The planar conformations of peptide bonds with the =0 and -H groups trans to each other contributes to the stability of the a helix. 

Krimm S, Bandekar J. Vibrational spectroscopy and conformation of peptides, polypeptides and proteins. Adv Protein Chem 1986 38 181-365. 

Because our research is focused on problems relevant to secondary structure of proteins in solution, this section will briefly review the recent developments in spectroscopic techniques applied to this problem. These techniques are considered low-resolution methods which provide global insight into the overall secondary structure of proteins without being able to establish the precise three-dimensional location of individual structural elements [707], Vibrational spectroscopy has played a pioneering role in studying the conformations of peptides, polypeptides, and proteins [702]. The advent of stable and powerful lasers has led to the development of Fourier transform methods which allows the use of powerful computational techniques for the analysis of spectral data [10,103,104], Laser... 

Besides stereoselective alkylations of glycine-derived enolates, enantioselective construction of chiral quaternary carbon centers from a-amino acids is one of the most challenging topics in current organic synthesis , since nonproteinogenic a,a-disubstituted amino acids often show a remarkable influence on the conformation of peptides. Moreover, they can act as enzyme inhibitors or as building blocks for the synthesis of a wide range of natural products . 

The most stable conformation of peptides that contain 3-amino-2-piperidone-6-carboxylic acid (22b), also an amino acid with a Ci -o- C i+i ring restriction, has been determined by H NMR (63). A chair conformation is a feature that characterizes the piperidone ring. Also, an intramolecularly H-bonded fS-turn form is the most plausible explanation for the experimental finding on these peptides. 

Kemp DS, McNamara P. Amino acid derivatives that stabiUze secondary structures of polypeptides. 11. The most stable conformation of peptides containing 3-amino-2-piperidone-6-carboxyUc acid (Acp). Tetrahedron Lett. 1982 23 3761-3764. 

Conformational restriction is a very powerful method for probing the bioactive conformations of peptides. Small peptides have many flexible torsion angles so that enormous numbers of conformations are possible in solution. For example, a simple tripeptide such as thyrotropin-releasing hormone (TRH 7) (Fig. 15.4) with six flexible bonds could have over 65,000 possible conformations. The number of potential conformers for larger peptides is enormous, and some method is needed to exclude potential conformers. Modem biophysical methods, e.g., X-ray crystallography or isotope edited nuclear magnetic resonance (NMR), (33) can be used to characterize peptide-protein interactions for soluble proteins, but most biophysical methods cannot yet determine the conformation of a ligand bound to constitutive receptors, e.g., G-protein-coupled receptors (34, 35). 

Kemmink, J. and Creighton, T. E. (1993). Lxical conformations of peptides representing the entire sequence of bovine pancreatic trypsine inhibitor. J. Mol. Biol., 234, 861-878. 

Table 5. Role of Sequence Variation and End Groups on the Solution Conformation of //-Peptides...

Vibrational Spectroscopy and Conformation of Peptides, Polypeptides, and Proteins... 

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