Mechanism of Action of Peptides That Cause the pH-Triggered Macromolecular Poration of Lipid Bilayers
Mechanism of Action of Peptides That Cause the pH-Triggered Macromolecular Poration of Lipid Bilayers
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DOI：
10.1021/jacs.9b01970
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发表时间：
2019-04-24
影响因子：
15
通讯作者：
Hristova, Kalina
中科院分区：
文献类型：
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作者：
Kim, Sarah Y.;Pittman, Anna E.;Hristova, Kalina
使用合成分子进化，我们以前发现了一个家族的肽，在低肽浓度下以酸性pH触发的方式在合成膜中引起大分子穿孔。为了理解这些“pHD肽”的作用机制，在这里，我们通过测量pH和肽浓度对膜结合，肽结构，以及膜中大分子大小的孔的形成。原子力显微镜和功能分析表明，肽诱导的外观大孔的双层。孔形成具有非常陡峭的pH依赖性，并且还依赖于肽浓度。在囊泡中，每1300个脂质中有1个结合肽或每个囊泡仅75个肽时，40 kDa右旋糖酐的50%泄漏，这一观察结果在广泛的酸性pH值范围内都成立。pH的主要作用是调节每个囊泡结合的肽的量。pHD肽的物理化学和序列影响其效力和pH依赖性;因此，本文所述的序列-结构-功能关系可用于特定应用的膜透化肽的未来设计和优化。
Using synthetic molecular evolution, we previously discovered a family of peptides that cause macromolecular poration in synthetic membranes at low peptide concentration in a way that is triggered by acidic pH. To understand the mechanism of action of these "pHD peptides", here we systematically explored structure-function relationships through measurements of the effect of pH and peptide concentration on membrane binding, peptide structure, and the formation of macromolecular-sized pores in membranes. Both AFM and functional assays demonstrate the peptide-induced appearance of large pores in bilayers. Pore formation has a very steep pH dependence and is also dependent on peptide concentration. In vesicles, 50% leakage of 40 kDa dextrans occurs at 1 bound peptide per 1300 lipids or only 75 peptides per vesicle, an observation that holds true across a wide range of acidic pH values. The major role of pH is to regulate the amount of peptide bound per vesicle. The physical chemistry and sequence of the pHD peptides affect their potency and pH dependence; therefore, the sequence-structure-function relationships described here can be used for the future design and optimization of membrane permeabilizing peptides for specific applications.