Department of Chemistry, University of Oslo, Postboks 1033 Blindern, 0315 Oslo, Norway.
Laboratory for Neutron Scattering and Imaging, Paul Scherrer Institut, Villigen 5232, Switzerland.
J Am Chem Soc. 2024 Jul 31;146(30):20891-20903. doi: 10.1021/jacs.4c05377. Epub 2024 Jul 17.
The formation of phase separated membrane domains is believed to be essential for the function of the cell. The precise composition and physical properties of lipid bilayer domains play crucial roles in regulating protein activity and governing cellular processes. Perturbation of the domain structure in human cells can be related to neurodegenerative diseases and cancer. Lipid rafts are also believed to be essential in bacteria, potentially serving as targets for antibiotics. An important question is how the membrane domain structure is affected by bioactive and therapeutic molecules, such as surface-active peptides, which target cellular membranes. Here we focus on antimicrobial peptides (AMPs), crucial components of the innate immune system, to gain insights into their interaction with model lipid membranes containing domains. Using small-angle neutron/X-ray scattering (SANS/SAXS), we show that the addition of several natural AMPs (indolicidin, LL-37, magainin II, and aurein 2.2) causes substantial growth and restructuring of the domains, which corresponds to increased line tension. Contrast variation SANS and SAXS results demonstrate that the peptide inserts evenly in both phases, and the increased line tension can be related to preferential and concentration dependent thinning of the unsaturated membrane phase. We speculate that the lateral restructuring caused by the AMPs may have important consequences in affecting physiological functions of real cells. This work thus shines important light onto the complex interactions and lateral (re)organization in lipid membranes, which is relevant for a molecular understanding of diseases and the action of antibiotics.
相分离膜域的形成被认为对细胞功能至关重要。脂质双层域的精确组成和物理性质在调节蛋白质活性和控制细胞过程中起着关键作用。人类细胞中域结构的扰动可能与神经退行性疾病和癌症有关。脂质筏也被认为在细菌中是必不可少的，可能成为抗生素的靶点。一个重要的问题是，生物活性和治疗性分子（如靶向细胞膜的表面活性剂肽）如何影响膜域结构。在这里，我们专注于抗菌肽 (AMP)，它们是先天免疫系统的重要组成部分，以深入了解它们与含有域的模型脂质膜的相互作用。使用小角中子/ X 射线散射 (SANS/SAXS)，我们表明，几种天然 AMP（吲哚素、LL-37、magainin II 和 aurein 2.2）的添加会导致域的大量生长和重构，这对应于线张力的增加。对比变化的 SANS 和 SAXS 结果表明，肽均匀地插入两相中，增加的线张力可归因于不饱和膜相的优先和浓度依赖性变薄。我们推测 AMP 引起的侧向重构可能会对影响真实细胞生理功能产生重要影响。这项工作因此为脂质膜中的复杂相互作用和侧向（重新）组织提供了重要的启示，这对于理解疾病和抗生素的作用的分子机制具有重要意义。
