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Issue 9, 2010
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Conformational ensembles of flexible β-turn mimetics in DMSO-d6

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Abstract

β-Turns play an important role in peptide and protein chemistry, biophysics, and bioinformatics. The aim of this research was to study short linear peptides that have a high propensity to form β-turn structures in solution. In particular, we examined conformational ensembles of β-turn forming peptides with a general sequence CBz-L-Ala-L-Xaa-Gly-L-Ala-OtBu. These tetrapeptides, APGA, A(4R)MePGA, and A(4S)MePGA, incorporate proline, (4R)-methylproline, and (4S)-methylproline, respectively, at the Xaa position. To determine the influence of the 4-methyl substituted prolines on the β-turn populations, the NAMFIS (NMR analysis of molecular flexibility in solution) deconvolution analysis for these three peptides were performed in DMSO-d6 solution. The NBO (natural bond orbital) method was employed to gain further insight into the results obtained from the NAMFIS analysis. The emphasis in the NBO analysis was to characterize remote intramolecular interactions that could influence the backbone-backbone interactions contributing to β-turn stability. NAMFIS results indicate that the enantiospecific incorporation of the methyl substituent at the Cγ (C4) position of the proline residue can be used to selectively control the pyrrolidine ring puckering propensities and, consequently, the preferred ϕ,ψ angles associated with the proline residue in β-turn forming peptides. The NAMFIS analyses show that the presence of (4S)-methylproline in A(4S)MePGA considerably increased the type II β-turn population with respect to APGA and A(4R)MePGA. The NBO calculations suggest that this observation can be rationalized based on an n→π* interaction between the N-terminus alanine carbonyl oxygen and the proline carbonyl group. Several other interactions between remote orbitals in these peptides provide a more detailed explanation for the observed population distributions.

Graphical abstract: Conformational ensembles of flexible β-turn mimetics in DMSO-d6

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Supplementary files

Article information


Submitted
19 Oct 2009
Accepted
19 Feb 2010
First published
11 Mar 2010

Org. Biomol. Chem., 2010,8, 2103-2116
Article type
Paper

Conformational ensembles of flexible β-turn mimetics in DMSO-d6

J. J. Koivisto, E. T. T. Kumpulainen and A. M. P. Koskinen, Org. Biomol. Chem., 2010, 8, 2103
DOI: 10.1039/B921794K

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