Center for Soft Condensed Matter Physics and Interdisciplinary Research, Soochow University, Suzhou 215006, PR China.
Institute for Frontier Materials, Deakin University, Geelong, Australia.
Biochim Biophys Acta Biomembr. 2018 Nov;1860(11):2234-2241. doi: 10.1016/j.bbamem.2018.09.007. Epub 2018 Sep 10.
Antimicrobial peptides (AMPs) provide a promising solution to the serious threat of multidrug-resistant bacteria or superbugs to public healthcare, due to their unique disruption to bacterial membrane such as perforation. Unfortunately, the underlying action mechanism of AMPs, especially the possible transition between the membrane binding and perforation states of peptides (i.e., the classical two-state model), is still largely unknown. Herein, by combining experimental techniques with pertinent membrane models and molecular dynamic (MD) simulations, new insights into the intermediate states of the AMP melittin-membrane interaction process are obtained. Specifically, it is demonstrated that, after the initial binding, the accumulated melittin on the bilayer triggers vigorous fluctuation of the membrane and even extracts some lipid molecules exclusively from the deformed outer leaflet of the bilayer. Such a distinctive mass removal manner and the resultant local asymmetry in lipid number between the two leaflets change the mechanical status of the membrane and in turn reduce the free energy barrier for the melittin insertion. Finally, the formation of the transmembrane pores is facilitated significantly. These findings provide new insights into the complicated antimicrobial mechanisms of AMPs.
抗菌肽 (AMPs) 为解决公共卫生领域中严重的耐多药细菌或超级细菌威胁提供了一种有前途的解决方案，这是因为它们对细菌膜具有独特的破坏作用，如穿孔。不幸的是，抗菌肽的潜在作用机制，特别是肽的膜结合和穿孔状态之间可能的转变（即经典的两态模型），在很大程度上仍然未知。在此，通过结合实验技术与相关的膜模型和分子动力学 (MD) 模拟，我们对 AMP 蜂毒素与膜相互作用过程中的中间状态获得了新的认识。具体来说，研究表明，在初始结合后，堆积在双层膜上的蜂毒素会引发双层膜的剧烈波动，甚至会从双层膜变形的外叶层中专门提取一些脂质分子。这种独特的质量去除方式和由此产生的双层膜中两个叶层之间脂质数量的局部不对称性改变了膜的力学状态，并反过来降低了蜂毒素插入的自由能障碍。最后，跨膜孔的形成得到了显著促进。这些发现为 AMP 的复杂抗菌机制提供了新的见解。
