Cis and trans peptide bond

The relevance of catalyzed and spontaneous peptide bond CTI to the biological function of peptides and proteins has inspired considerable effort in research. Thus, distinct pathways have been identified that allow peptide bond isomers to affect physiological signaling differently. To fully understand isomer specificity of bioreactions at the molecular level, it is essential to characterize the structural and electronic differences between cis and trans peptide bond isomers. Most importantly, both isomers cannot sample the same conformational space around proline [30,171], thus presenting an isomer-specific topography to interacting molecules. 

Fig. 5. Cis and trans peptide bonds as shown with N-acetyFN-methylaianine dimethylamide...

The conformational diaracteristics of cyclic hexapeptides containing sarcosine and/or proline are summarhEed in Table 9, which have been explained in the discussions described above. Peptide bonds involvii imino acid residues can take either cis or trans form. As a consequence, cis and trans peptide bonds distribute randomly along the peptide backbone, vii such complex NMR spectra as observed for Cyclo-(Sar ), Cyclo-(Sar-Sar-cyclic hexapeptides increased (Table 9). The introduction of ycine residue reduced the conformational multiplicity of the cyclic hexapeptides. 

And most importantly for a discussion of the replacement of amide bonds by fluoroolefin isosteres, the cis and trans amide bonds have different hydration shells [43,85]. The role of solvation and desolvation is understood to be crucial not only in amide bond isomerization but also in peptide transport generally. 

In cyclic peptides the cis- and frans-peptide bonds occur, with the cis form preferred in small cycles, and the trans form preferred in large systems (75AX(B)2035). The peptide bond is expected (68MI6) to deviate slightly from planarity in order to alleviate short-range interactions and bond-angle strain. 

In a similar fashion, it has been possible to isolate different conformations of the immunosuppressive drug, cyclosporin A. By preparing anhydrous THF solutions of CsA, with and without 0.4 M LiCl, it was possible to restrict the peptide ring system conformation in CsA to trans and cis conformers. Addition of these conformers separately to the assay buffer enabled the dissociation constants of both the cis and trans amide bond conformers in CsA for inhibition of PPIase to be determined. The trans conformer (2337t) is very active the cis conformer (23.37c) is not, and these plus other data were used to show that CsA adopts a conformation in water that is very close to the enzyme-bound CsA conformation. Subsequently, Wenger and coworkers at Sandoz (now Novartis) showed by NMR experiments that a 3-substituted CsA derivative, e.g. (23.38) (Fig. 23.8) adopts a conformation in water that is essentially identical... 

Two structurally unrelated immunosuppressant drugs, cyclosporin A and FK506, have been shown to bind to separate proteins, which have in common the ability to catalyse the interconversion (8) of the cis and trans rotamers of peptidyl-proline bonds of peptide substrates. A profound change in the conformation, and hence the shape and binding properties of the protein, may result. The mechanism of this isomerization appears, on the basis of recent work (Rosen et al., 1990 Van Duyne et al., 1993 Albers et al., 1990), to involve simple twisting about the amide bond, rather than such alternatives as conversion to a C-N single bond by addition of a nucleophile to C=0.y The proteins which catalyse the reaction may be... 

IR spectroscopy permits reliable discrimination between cis and trans-secondary amide bonds and the presence of 1550 cm bands is indicative of trans-peptide bonds (Table 2). 

Most peptide bonds in proteins take on the trans conformation (see p. 66). Only bonds with proline residues (-X-Pro-) can be present in both cis and trans forms. 

Even though the atoms within a peptide bond are coplanar, they can exist in two possible configurations, cis and trans ... 

Figure 1.3 The peptide bond. Distances are in A (1 A = 0.1 nm). Proline residues are found in both cis and trans conformations.

A large number of 13C NMR studies on proline derivatives and proline peptides have appeared in the literature [815-830]. As the electron charge density of cis-proline carbons is different from that of franx-prolinc carbons, these isomers can be differentiated by nCNMR spectroscopy [826, 830]. On the basis of calculations Tonelli [831] predicted four conformations for the dipeptide Boc-Pro-Pro-OBzl, three of which could be detected by 13C NMR spectroscopy [826, 830], In proline-containing peptides the stereochemistry of the proline residue plays an important role for the conformation of these oligomers. The 13C chemical shift data of cis and trans proline derivatives, collected in Table 5.29, are useful to determine the stereochemistry of the amino acid-proline bond, e.g. in cyclo-(Pro-Gly)3, melanocyte-stimulating hormone release-inhibiting factor or thyrotropin-releasing hormone. 

Figure 1 (Left) Model of the receptor-bound conformation of TIP containing all-trans peptide bonds (heavy lines) in spatial overlap with naltrindole (light lines). (Right) Model of the receptor bound conformation of H-Tyr-Tic-NH2 containing a cis peptide bond (heavy lines) in spatial overlap with naltrindole (light lines). In both cases the N-terminal amino group and the Tyr1 and Tic2 aromatic rings of the peptide are superimposed on the corresponding pharmacophoric moieties in the alkaloid structure.

In addition to the order-disorder transition, observed for a helices, helical structures can also be induced to undergo transitions from one ordered form to another. For example, a crystalline form of poly[p-(p-chlorobenzyl)-L-aspartate] can be made to undergo a phase transition from an a-helical to an co-helical form by heating rotational entropy is computed to play a role in this process.68 Another order-order transition is the solvent-induced interconversion between polyproline 1 (with cis peptide bonds) and polyproline 11 (with trans peptide bonds), a process that has also been subjected to conformational energy calculations.85 The transition has been accounted for in terms of differences in the binding of solvent components to the peptide 0=0 groups. 

The conformation of Xaa-Pro peptide bonds in the newly synthesized polypeptide chains prior to cellular folding is not known. The product of protein biosynthesis could be a uniform chain with all peptide bonds in the trans conformation. If this chain starts to fold immediately, then the trom-prolines would be in the correct conformation already, the cis-prolines would be in the incorrect isomeric state, and their trans — cis isomerization would be involved in the folding of all molecules. Alternatively, if there is sufficient time available for the Xaa-Pro bonds of the nascent chains to reach a cis/trans equilibrium (e.g., when folding is transiently arrested by binding to other proteins, such as heat-shock protein (HSP70), then the distribution of prolyl cis and trans isomers prior to cellular folding could be similar to the distribution found in the unfolded protein in vitro. Such a case was encountered in the maturation... 

Cydo-(Pro-Sai>-Gly)2 CDQ3 CD3OD DMSO 1 C2-symmetric conformation two -tums with two Gly-NH intra H-bond all trans peptide bonds 92% in CDQs, 88% in CD3OD, 76% in DMSO 1 asymmetric conformation one CIS and one trots Pro-Sai peptide bonds one intra and one inter Qy-NH H-boid... 

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