Electronic and Steric Control of n→π* Interactions: Stabilization of the α-Helix Conformation without a Hydrogen Bond.

Autor: Wenzell NA; Department of Chemistry and Biochemistry, University of Delaware, Newark, DE, 19716, USA., Ganguly HK; Department of Chemistry and Biochemistry, University of Delaware, Newark, DE, 19716, USA., Pandey AK; Department of Chemistry and Biochemistry, University of Delaware, Newark, DE, 19716, USA., Bhatt MR; Department of Chemistry and Biochemistry, University of Delaware, Newark, DE, 19716, USA., Yap GPA; Department of Chemistry and Biochemistry, University of Delaware, Newark, DE, 19716, USA., Zondlo NJ; Department of Chemistry and Biochemistry, University of Delaware, Newark, DE, 19716, USA.
Jazyk: angličtina
Zdroj: Chembiochem : a European journal of chemical biology [Chembiochem] 2019 Apr 01; Vol. 20 (7), pp. 963-967. Date of Electronic Publication: 2019 Mar 07.
DOI: 10.1002/cbic.201800785
Abstrakt: The preferred conformations of peptides and proteins are dependent on local interactions that bias the conformational ensemble. The n→π* interaction between consecutive carbonyls promotes compact conformations, including the α-helix and polyproline II helix. In order to further understand the n→π* interaction and to develop methods to promote defined conformational preferences through acyl N-capping motifs, a series of peptides was synthesized in which the electronic and steric properties of the acyl group were modified. Using NMR spectroscopy, van't Hoff analysis of enthalpies, X-ray crystallography, and computational investigations, we observed that more electron-rich donor carbonyls (pivaloyl, iso-butyryl, propionyl) promote stronger n→π* interactions and more compact conformations than acetyl or less electron-rich donor carbonyls (methoxyacetyl, fluoroacetyl, formyl). X-ray crystallography indicates a strong, electronically tunable preference for the α-helix conformation, as observed directly on the φ and ψ torsion angles. Electron-donating acyl groups promote the α-helical conformation, even in the absence of the hydrogen bonding that stabilizes the α-helix. In contrast, electron-withdrawing acyl groups led to more extended conformations. More sterically demanding groups can promote trans amide bonds independent of the electronic effect on n→π* interactions. Chloroacetyl groups additionally promote n→π* interactions through the interaction of the chlorine lone pair with the proximal carbonyl π*. These data provide additional support for an important role of n→π* interactions in the conformational ensemble of disordered or unfolded proteins. Moreover, this work suggests that readily incorporated acyl N-capping motifs that modulate n→π* interactions may be employed rationally to promote conformational biases in peptides, with potential applications in molecular design and medicinal chemistry.
(© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)
Databáze: MEDLINE
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