Helix, induction

These achiral poly(A -propargylamides) form helices with an equivalent amount of right- and left-handed screw senses. Addition of chiral alcohols induces predominantly one-handed screw sense in polyl7a and polyl7d. NMR spectroscopic analysis has revealed that the amide side chains interact with optically active alcohols by hydrogen bonding. Terpenes also induce a one-handed helix. In this case, hydrophobic interaction plays an important role for helix induction. 

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. 

Helix Induction Resulting from the Peptide Sequence... 

Helix induction can be augmented by mimicking natural mechanisms using a variety of synthetic expedients. In general, these approaches seek to either stabilize or mimic helix nucleation sites or to naturally or artificially secure side-chain linkages. In most cases, these transformations make use of additional synthetic procedures beyond standard peptide synthesis methodologies to juxtapose amino acids or essential elements thereof in a manner that mimics a protein helix. 

Nonpeptidic scaffolds may also be used to position carbonyl groups for the nucleation of helices. In the present case, three successive carbonyl groups are positioned in 3,6-dimethyl-4-oxo-2,3,4,5,6,7-hexahydro-l//-indole-3,6-dicarboxylic acid (11) (Scheme 5) to mimic those in the first turn of an a-helix.112" Peptide H-Glu-Ala-Leu-Ala-Lys-Ala-NH2 was attached to 11 through a linking residue and helix induction was examined by CD and NMR. 

There are few examples of C-terminal helix mimetics and, while their utility has been considered uncertain,11361 successful helix induction has been described using tetra-hydronaphthalene compounds represented by 16.11351 Templated peptide 17, for example, demonstrates 81% helix by CD while control peptide 18 exhibits only 50% helix under the same conditions (Scheme 7). For the preparation of tetrahydronaphthalene templates and their attachment to peptides, see refs.1134,1351... 

Helix Induction in Peptides by Addition of Metal Ions [1761... 

Chelation of 32 with the 17-residue peptides 33 and 34 (Scheme 20) results in up to 80 and 50% helix, respectively, at 21 °C, as measured by CD spectroscopy. Without the metal complex, 33 is 45% helical, while uncomplexed 34 exhibits the CD spectrum of a random coil structure.11771 Helix induction results from the loss of conformational flexibility of the peptides upon complexation. 

As mentioned above, these three subunits were designed to form a first a-helical turn in which the four amide groups are ideally oriented to participate in the H-bond network of an a-helix. Peptides that are linked to these templates adopt an a-helical conformation due to the conformational constraint induced by the high inherent a-helix propensity of the template and the H-bond network that is initiated by the proper orientation of the carbonyl groups. Thus, helix induction is achieved by the combination of steric and electronic properties of the three subunits. 

A careful analysis of conformational energy maps (Ramachandran plots) revealed that both enantiomers of P-tetralin amino acids were compatible with the right handed a-helical conformation.109 This was an important prerequisite for the development of N- and C-caps since the ( -configuration of the P-tetralin amino acid is needed for N-terminal helix induction, whereas the (R)-enantiomer was used in the C-cap series. The fact that both configurations were compatible with a-helical conformations made these amino acids our first choice as building blocks for... 

The fact that both N- and C-terminal a-helix induction was achieved using the same concept raised the question of whether it would be possible to combine the N- and C-cap concepts, by generating a position-independent template that stabilizes (J-helical conformations not only from N-terminal or C-terminal ends but also from internal positions. 

In comparison to N- and C-caps, position-independent templates potentially offer significant advantages. Incorporated at internal positions, these templates are supposed to transmit the conformational information along the helix axis towards both termini of the peptide. If the helix induction potential is comparable to that observed for N- and C-caps, position-independent templates at internal positions might stabilize up to five consecutive a-helical turns, or peptides with 18 amino acids.202... 

The template has to bear H-bond acceptors for N-terminal—as well as H-bond donors for C-terminal helix induction. 

In order to show that HIT-1 was a-helix compatible and induces a-helical conformations in short peptides from the N- and C-terminus as well as from internal positions, template-linked peptides have been compared to nonconstrained reference peptides. In the N- and C-cap projects a hydrophobic 12-mer peptide was used as a standard reference. The 12-mer reference peptide 104 was originally developed for host guest experiments to evaluate the a-helix propensities of unnatural amino acids (see Section II.A) and had later been used to confirm N-cap induced helix formation.141,202,214 In the C-cap series and for position-independent templates the same reference peptide could be used after minor modification of the terminal protection groups. The suitably protected reference peptide and the corresponding template-linked model peptides used for the evaluation of N-terminal, C-terminal, and internal helix induction are depicted in Figure 39. 

HIT-linked peptides proved to be valuable tools to assess the a-helix induction potential of HIT-1. CD measurements revealed that HIT-1 has a high a-helix inducing potential at the N-terminus. Incorporated at internal positions, HIT-1 proved to be a moderate a-helix inducer and it strongly initiated the formation of 310-helical conformations once incorporated at the C-terminus. Based on these results, and for reasons of chemical stability, we replaced the (/ )-serine linker by the more rigid and a-helix compatible (/ )-a-methylserine analogue.203... 

Figure 39. Reference peptides (first row) template-linked model peptides (second row) used for the evaluation of N-terminal, C-terminal internal a-helix induction.

Chiral amplification phenomena of sergeants and soldiers and majority rule effects, which are characteristic features for dynamic helical polymers [4,58], are, therefore, observed for the noncovalent helix induction in the poly(phenylacetylene)s. For example, when 28 was mixed with 50% ee of 2-amino-1-propanol in DMSO, the complex showed an intense ICD like that of 100% ee. In the presence of a small amount of (R)-39, 28 showed a very weak ICD due to the lack of a single-handed helical conformation. However, the coaddition of the excess bulky, achiral 1-naphthylmethylamine 40 with... 

Fig. 20 Schematic illustration of a predominant one-handed helix induction in 60 by inclusion complex formation with a chiral guest molecule 61...

Fig. 22 a Schematic illustration of a predominantly one-handed helix induction in 66 upon complexation with chiral carboxylic acids, b Expected hydrogen-bonding modes... 

In the case of 105, carbohydrates and steroids induced the helicity.187 A reverse combination of acid and base compared to the helix induction using 104 was achieved using 106, whose interaction with various chiral carboxylic acids led to an excess screw sense of the main chain.188,189... 

These conclusions were drawn from the X-ray structures of some of the hydrox-ylated prolines and related N-acetyl methyl ester derivatives [39,40] as well as from the thermodynamic parameters obtained by NMR conformational analysis of the model compounds Ac-Pro -OMe, with Pro corresponding to 1-4 [15,21,32], and Ac-Phe-Pro -NHMe, with Pro being 1-5 (Tables 11.1 and 11.2) [41], While O-acetylation or O-trifluoroacetylation of the 4-hydroxyproline increases the inductive effects [40], and thus stabilizes the O-exo pucker and trans-conformation of aminoacyl-Hyp bonds, unfavorable steric interactions reduce these effects in terms of triple-helix induction and stability [40]. In addition, Table 11.2 reports the thermodynamic parameters of (3R,4S)-Dhp (6) which displays a similar behavior... 

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