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Multiple Conformational States in Crystals and in Solution in \alpha\gamma Hybrid Peptides. Fragility of the $C_{12}$ Helix in Short Sequences

Chatterjee, Sunanda and Vasudev, Prema G and Ananda, Kuppanna and Raghothama, Srinivasarao and Shamala, Narayanaswamy and Balaram, Padmanabhan (2008) Multiple Conformational States in Crystals and in Solution in \alpha\gamma Hybrid Peptides. Fragility of the $C_{12}$ Helix in Short Sequences. In: Journal of Organic Chemistry, 73 (17). pp. 6595-6606.

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The conformational properties of foldamers generated from \alpha\gamma hybrid peptide sequences have been probed in the model sequence Boc-Aib-Gpn-Aib-Gpn-NHMe. The choice of R-aminoisobutyryl (Aib) and gabapentin (Gpn) residues greatly restricts sterically accessible conformational space. This model sequence was anticipated to be a short segment of the \alpha\gamma $C_{12}$ helix, stabilized by three successive $4\rightarrow 1$ hydrogen bonds, corresponding to a backbone-expanded analogue of the \alpha polypeptide $3_{10}$-helix. Unexpectedly, three distinct crystalline polymorphs were characterized in the solid state by X-ray diffraction. In one form, two successive $C_{12}$ hydrogen bonds were obtained at the N-terminus, while a novel $C_{17}$ hydrogenbonded \gamma\alpha\gamma turn was observed at the C-terminus. In the other two polymorphs, isolated $C_9$ and $C_7$ hydrogen-bonded turns were observed at Gpn (2) and Gpn (4). Isolated $C_{12}$ and $C_9$ turns were also crystallographically established in the peptides Boc-Aib-Gpn-Aib-OMe and Boc-Gpn-Aib-NHMe, respectively. Selective line broadening of NH resonances and the observation of medium range $NH(i) \leftrightarrow NH(i+2)$ NOEs established the presence of conformational heterogeneity for the tetrapeptide in $CDCl_3$ solution. The NMR results are consistent with the limited population of the continuous $C_{12}$ helix conformation. Lengthening of the $(\alpha\gamma)_n$ sequences in the nonapeptides Boc-Aib-Gpn-Aib-Gpn-Aib-Gpn- Aib-Gpn-Xxx (Xxx) Aib, Leu) resulted in the observation of all of the sequential NOEs characteristic of an \alpha\gamma $C_{12}$ helix. These results establish that conformational fragility is manifested in short hybrid \alpha\gamma sequences despite the choice of conformationally constrained residues, while stable helices are formed on chain extension.

Item Type: Journal Article
Publication: Journal of Organic Chemistry
Publisher: American Chemical Society
Additional Information: Copyright of this article belongs to American Chemical Society.
Department/Centre: Division of Biological Sciences > Molecular Biophysics Unit
Division of Chemical Sciences > NMR Research Centre (Formerly Sophisticated Instruments Facility)
Division of Physical & Mathematical Sciences > Physics
Date Deposited: 18 Oct 2008 13:38
Last Modified: 19 Sep 2010 04:51
URI: http://eprints.iisc.ac.in/id/eprint/16138

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