Key Centre for Polymers & Colloids, The University of Sydney, School of Chemistry, Building F11, Sydney NSW 2006, Australia.
Org Biomol Chem. 2015 Feb 28;13(8):2464-73. doi: 10.1039/c4ob02041c.
The effect of amino acid composition on the formation of transmembrane channels in lipid bilayers upon self-assembly of alt-(L,D)-α-cyclic octapeptides has been investigated. Cyclic peptides comprising D-leucine, alternating with different combinations of L-azidolysine, L-lysine(Alloc), L-lysine and L-tryptophan were synthesized and the size of pores formed via self-assembly of these molecules in lipid bilayers was elucidated using large unilamellar vesicle fluorescence assays and dynamic light scattering. Pore formation was examined in large unilamellar vesicles made up of egg yolk phosphatidylcholine or Escherichia coli total lipid extract. From these analyses, we have established that cyclic peptides with charged side chains form large pores while those with neutral side chains form unimeric pores. Furthermore, the cyclic peptides that consist of non-symmetric amino acid configurations possess a higher membrane activity than the cyclic peptides with a symmetric amino acid configuration. In addition, we have found that peptide amphiphilicity plays a vital role in selective partitioning between bilayers that consist of egg yolk phosphatidylcholine and those comprised of E. coli total lipid extract. These results suggest that selective transbilayer channel formation via self-assembly may be a viable alternative for many applications that currently use more expensive, multistep synthesis methods.
研究了在自组装 alt-(L,D)-α-环八肽时，氨基酸组成对脂质双层中形成跨膜通道的影响。合成了由 D-亮氨酸组成、与不同 L-叠氮赖氨酸、L-赖氨酸（Alloc）、L-赖氨酸和 L-色氨酸组合交替的环肽，并使用大单层囊泡荧光测定法和动态光散射法阐明了这些分子在脂质双层中自组装形成的孔的大小。通过自组装形成的孔在由蛋黄卵磷脂或大肠杆菌总脂提取物组成的大单层囊泡中进行了检查。通过这些分析，我们已经确定带电荷侧链的环肽形成大孔，而带中性侧链的环肽形成单体孔。此外，由非对称氨基酸构型组成的环肽比具有对称氨基酸构型的环肽具有更高的膜活性。另外，我们发现肽两亲性在由蛋黄卵磷脂组成的双层和由大肠杆菌总脂提取物组成的双层之间的选择性分配中起着至关重要的作用。这些结果表明，通过自组装选择性跨膜通道形成可能是许多当前使用昂贵的多步合成方法的应用的可行替代方案。
