Li Jia, Lu Xuemei, Ma Wendong, Chen Zhonglan, Sun Shuqing, Wang Qinghui, Yuan Bing, Yang Kai
Electric and Informative Engineering School, Yunnan Minzu University, Kunming, China.
Wenzheng College of Soochow University, Suzhou, China.
Front Mol Biosci. 2021 Feb 3;8:638988. doi: 10.3389/fmolb.2021.638988. eCollection 2021.
The existing cholesterols (Chols) in animal cell membranes play key roles in many fundamental cellular processes, which also promise the possibility to modulate the bioactivity of various membrane-active biomacromolecules. Here, combining dynamic giant unilamellar vesicle leakage experiments and molecular dynamics simulations, the inhibitory effect of Chols on the membrane poration activity of melittin (Mel), a typical natural antimicrobial peptide, is demonstrated. Molecular details of the Mel-Chol interactions in membrane show that, for a Chol-contained lipid membrane, Mel exposure would perturb the symmetric bilayer structure of the membrane and specifically influence the location and orientation distributions of Chol molecules to an asymmetric state between the two leaflets; moreover, the Mel-Chol interactions are significantly influenced by the membrane environment such as unsaturation degree of the lipid components. Such inhibitory effect is normally ascribed to an accumulation of Chol molecules around the membrane-bound peptide chains and formation of Chol-Mel complexes in the membrane, which hinder the further insertion of peptides into the membrane. This work clarifies the molecular interactions between membrane-active peptides and Chol-contained membranes, and suggest the possibility to develop targeted drugs due to the membrane component specificity between bacterial and animal cells.
动物细胞膜中现有的胆固醇（Chols）在许多基本细胞过程中发挥着关键作用，这也为调节各种膜活性生物大分子的生物活性提供了可能性。在此，结合动态巨型单层囊泡泄漏实验和分子动力学模拟，证明了胆固醇对典型天然抗菌肽蜂毒素（Mel）的膜穿孔活性具有抑制作用。膜中Mel-Chol相互作用的分子细节表明，对于含胆固醇的脂质膜，Mel的暴露会扰乱膜的对称双层结构，并特别影响胆固醇分子在两个小叶之间的位置和取向分布，使其处于不对称状态；此外，Mel-Chol相互作用受到膜环境（如脂质成分的不饱和度）的显著影响。这种抑制作用通常归因于胆固醇分子在膜结合肽链周围的积累以及膜中Chol-Mel复合物的形成，这阻碍了肽进一步插入膜中。这项工作阐明了膜活性肽与含胆固醇膜之间的分子相互作用，并表明由于细菌和动物细胞之间的膜成分特异性，有可能开发靶向药物。
