Helical peptides

Fig. 2.39 Schematic representation of the projection of idealized ji- and y-peptide helices in a plane perpendicular to the helix axis and comparison with the helical wheel of the natural a-helix...

The measurements of chain stiffness of denatured proteins are made in the presence of a strong denaturant, such as 8 M urea or 6 M GdmCl, in which peptide H-bonds are weak and peptide helices unfold (Scholtz et al., 1995 Smith and Scholtz, 1996), and the possible presence of (/-helices or /3-hairpins is not an issue in these denaturants. The careful and thorough measurements of intrinsic viscosities made by Tanford and co-workers (1968), discussed above, yield a substantially lower estimate for chain stiffness than the work of Flory and co-workers. A comparison is made by Tanford (1968) between the proportionality coefficient... 

Dieckmann GR, Dalton AB, Johnson PA, Razal J, Chen J, Giordano GM, Munoz E, Musselman IH, Baughman RH, Draper RK (2003) Controlled assembly of carbon nanotubes by designed amphiphilic peptide helices. J. Am. Chem. Soc. 125 1770-1777. 

It is now well accepted that the residues making up the peptide sequence, their position at the beginning, middle, and ends of helices, the context in which they occur relative to other residues, as well as peptide length and environment, all influence helix induction and stability. In forming peptide helices, careful planning of the sequence is essential and all these factors have to be taken into account. Section 12.3.1.1 presents many of these factors to consider for inducing helix formation without the use of synthetic appendages. 

Of all the amino acids, Ala has the highest tendency to adopt an a-helical conformation based on the Chou and Fasman rules for secondary structure prediction181 and host-guest determination of helical propensities/181 This has also been demonstrated in studies by Marqusee et al. on short alanine-based peptides which were found to form stable monomeric peptide helices in water/191... 

While exploring alternative i, i + 7 side-chain bridges, Yu and Taylor[164] linked an Ampa residue by amide bond formation to the side chain of a Dap residue at the N-terminal, i position, and an Asp residue at the C-terminal, i + 7 position. CD studies indicated that peptide helicity can be improved from an estimated 12% for an acyclic control peptide to 47% in aqueous phosphate buffer at 25 °C. This is similar to that of a comparable peptide with two i, i + 4 Lys- - Asp bridges (41% helix) J164]... 

This volume focuses on extensions of peptide chemistry into the novel areas of template-conjugated peptides, helical arrays of polypeptides, dendrimers, and C-terminally modified peptides. The volume concludes with an overview of the classic syntheses of representative peptide natural products. 

As one example, the observation of hydrogen bonding [7] in natural systems such as peptide helices and DNA base pairs led to a theoretical understanding of this phenomenon. This understanding has permitted the use of hydrogen bonding in synthesis, leading to the preparation of such diverse structures as Rebek s capsules [8], Lehn s supramolecular polymers [9], and Whitesides rosettes [10]. 

Figure 8. A p -nonapetide, which has been shown to be capable of mimicking an amphiphilic a-peptidic helical structure in a pepide-protein interaction [26], was C-labeIled and injected into rats. After 24 hours (in serum, not shown) and after 4 days (in urine and in feces the minor and major secretion pathways, respectively), there was hardly any metabolism, see the HPLC chromatograms with radiodetection (DSPOl is the compound, the formula of which is shown above) [68],...

K. Gadematm, B. Jaun, D. Seebach, R. Peiozzo, L. Scapozza, G. Folkers, Temperature-Dependant NMR and CD Spectra of p-Peptides. On the Thermal Stability of P-Peptide Helices -Is the Folding Process of p-Peptides non-cooperative , Helv. Chim. Acta, 1999,82,1 - 11. 

A. Jacobi, D. Seebach, How to Stabilize or Break P-Peptidic Helices by Disulfide Bridges Synthesis and CD Investigation of P-Peptides with Cysteine and Homocysteine Side Chains Helv. Chim. Acta 1999, 82, 1150- 1172. 

Table 1 Relevant average parameters for peptide helices based on L-configurated a-amino acids discussed in this review article...

Two (parallel and perpendicular to the helix axis) views for each of the three fl-peptide helices discussed in this section are presented in Fig. 7. Recent applications of -peptide helices to relevant biological issues (antibacterial activity, transport across cell membranes) (48-51) will certainly stimulate additional work in this promising area. 

Figure 45. Retroanalysis of y-peptide helices twist sense.

Ara-vinda, S., Shamala, N., Bandyopadhyay, A., and Balaram, P. (2003) Probing the role of the C H- - -O hydrogen bond stabilized polypeptide chain reversal at the C-terminus of designed peptide helices. Structural characterization of three decapeptides, J. Am. Chem. Soc. 125, 15065-15075. 

Blackwell HE, Grubbs RH (1998) Highly efficient synthesis of covalently cross-linked peptide helices by ring-closing metathesis. Angew Chem Int Ed Engl 37 3281-3284... 

Fig. 13 Stabilized helices and nonnatural helix mimetics several strategies that stabilize the a-helical conformation in peptides or mimic this domain with nonnatural scaffolds have been described. Recent advances include [1-peptide helices, terphenyl helix-mimetics, mini-proteins, peptoid helices, side-chain crosslinked a-helices, and the hydrogen bond surrogate (HBS) derived a-helices. Circles represent amino acid side-chain functionality (Reprinted from Henchey et al. [52], Copyright (2008) with permission from Elsevier)...

Quadruple peptide helices have also been made by self-assembly in water. The designed amino acid 16-meric sequence GELEELLKKLKELLKG forms an amphiphilic helix and should form a four-helix bundle or quadruple helix by assembly of the hydrophobic leucine segments. It was indeed found experimentally that the ellipticity in the CD spectrum increased with the fourth power of the peptide concentration. The helices were only formed if there was a chance of tetramerization (Eisenberg et al., 1986). 

Botan V, Backus EHG, Pfister R, Moretto A, Crisma M, Toniolo C, Nguyen PH, Stock G, Hamm P. 2007. Energy transport in peptide helices. Proc. Natl. Acad. Sci. U. S. A. 104 12749-12754. 

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