Verheyden P, Jaspers H, De Wolf E, Van Binst G
Department of Organic Chemistry, Free University of Brussels, Belgium.
Int J Pept Protein Res. 1994 Oct;44(4):364-71. doi: 10.1111/j.1399-3011.1994.tb01021.x.
The conformation of cyclosporin A (CsA), an undecapeptide with seven N-methylated amino acids, was studied in acetone at 193 K. Previous studies of the conformation of CsA in different solvents, in the cyclosporin-cyclophilin complex and in complexes with LiCl showed that the conformation of the free and the bound CsA are different. Differences were observed at the conformation of the MeLeu9-MeLeu10 peptide bond, which is cis in solution and trans in the complex, and in the orientation of the amide protons and the N-Me groups. By using acetone, which is a proton acceptor, we wanted to influence the orientation of the amide protons. In the conditions used in this study a new conformation is found, which differs as well from the one previously observed in solution as from the conformation observed in the complex. This conformation has a cis peptide bond between MeLeu9 and MeLeu10. The trans conformation of the peptide bond MeLeu9-MeLeu10, which is necessary for biological activity, was not induced. One of the amide protons is involved in an intramolecular H-bridge stabilising a beta-turn around Sar3MeLeu4, and three of the seven NMe groups are oriented to the centre of the molecule.
在193K的丙酮中研究了环孢菌素A（CsA）的构象，它是一种含有七个N-甲基化氨基酸的十一肽。先前对CsA在不同溶剂中、在环孢菌素-亲环蛋白复合物中以及与LiCl形成的复合物中的构象研究表明，游离态和结合态的CsA构象不同。在MeLeu9-MeLeu10肽键的构象上观察到差异，该肽键在溶液中为顺式，在复合物中为反式，并且在酰胺质子和N-Me基团的取向上也存在差异。通过使用作为质子受体的丙酮，我们希望影响酰胺质子的取向。在本研究使用的条件下发现了一种新的构象，它既不同于先前在溶液中观察到的构象，也不同于在复合物中观察到的构象。这种构象在MeLeu9和MeLeu10之间有一个顺式肽键。对生物活性至关重要的MeLeu9-MeLeu10肽键的反式构象并未被诱导出来。其中一个酰胺质子参与了分子内氢键，稳定了围绕Sar3MeLeu4的β-转角，并且七个NMe基团中的三个朝向分子中心。
