Proline, conformational properties

CD and ORD have also been employed to detect conformational properties of acyl heterocycles in optically active molecules especially in biological systems. These techniques have been employed, for example, in the conformational study of proline derivatives (70MI2 70M13 73BCJ3894), and as complementary approaches to NMR measurements. 

N-Acylpipecolic acids 120 were examined to compare the conformational properties of piperidine-2-carboxylic acid to those of the parent proline molecule. In the N-acetyl derivative (120, R = Me), the s-cis ( ) form is more stable (72CC788) in the solid state and less stable in the equilibrium mixture in solution, with the s-cis/s-trans ratio varying with the pH of the... 

N 032 "Conformational Properties of Poly(L-proline) Form II in Dilute Solution"... 

The characteristic ratios of poly(pro-gly), poly(hyp-gly), poly(gly-gly-pro-gly), poly(gly-gly-hyp-gly), and poly(pro-ale) are determined in water, The results confirm the main features of the theoretical conformational maps derived by Rory and coworkers for glycine followed by either l-proline or a nonproline residue. Small adjustments, well within the uncertainty described by Schimme and Rory, are suggested In the conformational map for L-proline followed by glycine. The constants for the Lennard-Jones functions of Scheraga and coworkers, as used by Madison and Scheliman, produce a conformational map for L-proline followed by a nonproline residue which is in somewhat poorer agreement with experiment. The two sets of modified constants introduced by Madison and Scheliman fall to predict the conformational properties of these sequential copolypeptides. 

Conformational Properties of Poly(y-hydroxy-L-proline) Based on Rigid and Flexible Pyrrolidine Rings"... 

The conformations of several N-acyl-L-prolines were studied by CD and nmr (Nishihara et a/., 1975), and it was found that JV-acetyl-L-proline has two rotational isomers (S-trans and S-cis) about the amide bond. The two rotamers show CD Cotton effects of opposite sign associated with the n-7C transition of the amide moiety. The chiroptical properties of L-proline conformational isomers were examined on a theoretical model, and spectra-structure correlations were proposed for the anionic and cationic forms of L-proline in solution (Madison and Schellman, 1970b Richardson and Ferber, 1977). 

In order to better understand the importance of substrate conformation to enzymatic N-glycosylation, a study was carried out comparing the solution conformation and glycosyl acceptor properties of a series of tripeptides of the general sequence Ac-Asn-Xaa-Thr-NH2 (76). Several amino acids with very distinct conformational properties were substituted in the middle position alanine, leucine, aspartic acid, proline, D-alanine, and a-aminoisobutyric acid. One and two dimensional iH NMR studies were used to determine intramolecular hydrogen bonding patterns, and NOE connectivities. 

T. P. Creamer (unpublished results). A plot of estimated (ASA) against %PPII content is given in Figure 5. At first glance, it would appear that there is little correlation between the two properties. However, three residues—proline, glycine, and glutamine—can be considered outliers, each for a specific reason. Proline has a high %PPII content in the polyproline-based host peptide used by Kelly et al. (2001) as a result of its unique properties as an imine. As discussed above, a proline that is followed in sequence by a second proline is restricted to the PPII conformation by steric interactions. 

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... 

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." ... 

The properties of polypeptides and proteins are determined to a large extent by the chemistry of the side chain groups, which may be summarized briefly as follows. Glycine in a peptide permits a maximum of conformational mobility. The nine relatively nonpolar amino acids-alanine, valine, leucine, isoleucine, proline, methionine, phenylalanine, tyrosine, and tryptophan-serve as building blocks of characteristic shape. Tyrosine and tryptophan also participate in hydrogen bonding and in aromatic aromatic interactions within proteins. 

As in the case of the five-membered proline analogues, besides pipecolic acid (6) as the six-membered homologue of proline, related aza-, oxa-, and thia-analogues are used to mimic the conformationally restricting properties of proline in the peptidomimetic design of bioactive compounds.1202 ... 

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