Turn structural conformation

The two /3-turn structures, pc and Pe are the most stable among those considered. This is in accord with the unconstrained nanosecond simulations of linear DPDPE, which converged to these conformers [14]. Because the cyclic form is relatively rigid, it is assumed that the conformation it adopts in solution is the biologically active one, responsible for its high affinity and specificity towards the 5 opioid receptor. The relatively low population of the cyclic-like structure for the linear peptide thus agrees qualitatively with the... 

Robust peptide-derived approaches aim to identify a small drug-like molecule to mimic the peptide interactions. The primary peptide molecule is considered in these approaches as a tool compound to demonstrate that small molecules can compete with a given interaction. A variety of chemical, 3D structural and molecular modeling approaches are used to validate the essential 3D pharmacophore model which in turn is the basis for the design of the mimics. The chemical approaches include in addition to N- and C-terminal truncations a variety of positional scanning methods. Using alanine scans one can identify the key pharmacophore points D-amino-acid or proline scans allow stabilization of (i-turn structures cyclic scans bias the peptide or portions of the peptide in a particular conformation (a-helix, (i-turn and so on) other scans, like N-methyl-amino-acid scans and amide-bond-replacement (depsi-peptides) scans aim to improve the ADME properties." ... 

Unfortunately, direct Ugi reaction of 85 predominantly led to the formation of DHOPs (87) [172]. However, by applying a MCR-alkylation-MCR strategy, the Ugi products (88) could be isolated in high yields [173]. The obtained conformationally constrained peptidomimetics allow for unprecedented diversification and were ultimately evaluated for their turn-inducing properties, indicating an open turn structure for 88a (Fig. 27). 

NMR and kinetic studies have been conducted with the hope of providing more details about the position and conformation of the polypeptide substrate in cAMP-dependent protein kinase. These have served to narrow down the possible spatial relationships between enzyme bound ATP and the phosphorylated serine. Thus, a picture of the active site that is consistent with the available data can be drawn (12,13,66,67). Although these studies have been largely successful at eliminating some classes of secondary polypeptide structure such as oi-hellces, 6-sheets or an obligatory 6-turn conformation 66), the precise conformation of the substrate is still not known. The data are consistent with a preference for certain 6-turn structures directly Involving the phosphorylated serine residue. However, they are also consistent with a preference or requirement for either a coil structure or some nonspecific type of secondary structure. Models of the ternary active-site complexes based on both the coil and the, turn conformations of one alternate peptide substrate have" been constructed (12). These two models are consistent with the available kinetic and NMR data. 

Stabilization of a P-hairpin structure can be achieved in two ways, promoting a stable (or restricted) turn structure (as done with mimetics) or linking the two arms either chemically, or, more naturally, by hydrophobic interactions. In an approach to utilizing both methods, a D-Pro-Gly linkage was used to stabilize a left-handed turn (type I or II ) and various charged and hydrophobic residues were used to stabilize the molecule and enhance the interaction between arms. I252"254 Examples of these peptides studied in nonaqueous solution by IR, VCD and NMR spectroscopy exhibit characteristics of well-formed hairpins. 255 Alternatively, in aqueous solution, IR, VCD, and ECD results for related peptides agree with the NMR interpretation of conformations characterized as hairpins stabilized at the turn and frayed at the ends. 256 These latter results also have a qualitative match with theoretical simulations. Recently, examples of hydrophobically stabilized hairpins studied by NMR spectroscopy have avoided use of a nonnatural amino acid. 257,258 ... 

The RGD sequence was thus constrained into a variety of sheet or /3-turn structures, which were unequivocally determined for each peptide. The biological activity of 18 cyclic peptides was then compared with that of a linear standard, GRGDS, in inhibition assays of tumour cell adhesion. An increase in activity of up to 100-fold was observed for just two cyclic pentapeptides, all others showing a decrease in activity. This identified the required conformation of the RGD backbone. 

By theoretical conformational analysis the me/a-isomer (m-Abz) has been shown to provide distances between the amino and the carboxy functions that are in the range of those accessible to a tram dipeptide.121 22 The conformational flexibility is quite different, however, and turn structures are excluded. 23 ... 

Further constraint of the aminomethyl chain has been performed by incorporating it into 5,6,7,8-tetrahydronaphthoic acids 19 and 20 (Scheme 7) 5961 731 X-ray diffraction and NMR analysis of the TV-acetyl-jV -isopropylamide 21 revealed that the compound induces a turn structure without the formation of an intramolecular hydrogen bond. However, molecular modeling studies indicate that this amino acid derivative prefers a partially extended conformation 71,72 ... 

Methano amino acids 6 and 7 (Scheme 6), which have rigidly defined x1 orientations, have been utilized by several groups and shown to induce y-turn structures. Incorporation of (25,35)-c-Met 7 into the anti-opiate peptide H-Phe-Met-Arg-Phe-NH2 (with replacement of the Met residue) using solid-phase synthesis provided an analogue whose lowest energy conformation involved a y-turn centered around the c-Met residue (Scheme 6)J32 ... 

An inverse y-turn mimetic, containing a 3-morpholinone ring 23 (Scheme 14) as the key structural feature was prepared enantiospecifically.[43] Molecular mechanics calculations revealed that the torsional angles of the second residue of the mimetic were effectively constrained in an inverse y-turn-like conformation. 

In this section, the general 3-sheet/ 3-turn structural motif of gramicidin S has been utilized as the basis of molecular scaffolds which can present desired sequences in (3-sheet conformations. It should be noted however that not all sequences incorporated within this template will lend themselves to forming the same 3-sheet/ 3-tum structure as found in gramicidin S. 

These findings agree well with the results obtained from 2D-NMR measurements. NOE measurements revealed that not only the template itself, but also the second helical turn adopted a well defined a-helical conformation. In the third turn, the conformation was more flexible but a-helical conformations still predominate. Furthermore, the X-ray structure of the same N-capped model peptide revealed that the peptide is fully a-helical in the solid state (see Figure 33). Figure 34 schematically shows a retrosynthetic analysis of the N-caps. 

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