Department of Chemistry and Biochemistry, University of Delaware, Newark, DE, 19716, USA.
Chembiochem. 2019 Apr 1;20(7):963-967. doi: 10.1002/cbic.201800785. Epub 2019 Mar 7.
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.
肽和蛋白质的优势构象取决于局部相互作用，这些相互作用会影响构象的整体分布。羰基之间的 n→π相互作用促进了紧凑的构象，包括α-螺旋和聚脯氨酸 II 螺旋。为了进一步了解 n→π相互作用，并开发通过酰基 N-封端基序促进明确构象偏好的方法，我们合成了一系列酰基电子和空间性质被修饰的肽。通过 NMR 光谱、焓的范特霍夫分析、X 射线晶体学和计算研究，我们观察到，电子供体羰基（特戊酰基、异丁酰基、丙酰基）比乙酰基或电子供体羰基（甲氧羰基、氟乙酰基、甲酰基）具有更强的 n→π相互作用和更紧凑的构象。X 射线晶体学表明，即使在没有稳定α-螺旋的氢键的情况下，也存在对α-螺旋构象的强烈、电子可调的偏好，这可以直接从 φ 和 ψ 扭转角观察到。供电子酰基基团促进α-螺旋构象，即使在没有稳定α-螺旋的氢键的情况下。相比之下，吸电子酰基基团导致更伸展的构象。空间位阻较大的基团可以独立于 n→π相互作用的电子效应促进反式酰胺键。氯乙酰基基团通过氯孤对与临近羰基 π的相互作用进一步促进 n→π相互作用。这些数据为 n→π相互作用在无规或去折叠蛋白质构象整体中的重要作用提供了额外的支持。此外，这项工作表明，可合理引入调节 n→π相互作用的酰基 N-封端基序，可能会在肽中促进构象偏向，这在分子设计和药物化学中有潜在的应用。
