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首页> 外文期刊>Biochemistry >Mechanism of Antibacterial Action of Dermaseptin B2: Interplay between Helix−Hinge−Helix Structure and Membrane Curvature Strain
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Mechanism of Antibacterial Action of Dermaseptin B2: Interplay between Helix−Hinge−Helix Structure and Membrane Curvature Strain

机译：Dermaseptin B2抗菌作用的机制：螺旋-铰链-螺旋结构和膜曲率应变之间的相互作用。

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Dermaseptin B2 (Drs B2) is a 33-residue-long cationic, -helical antimicrobial peptide endowednwith membrane-damaging activity against a broad spectrum of microorganisms, including bacteria, yeasts,nfungi, and protozoa, but its precise mechanism of action remained ill-defined. A detailed characterizationnof peptide membrane interactions of Drs B2 was undertaken in comparison with a C-terminal truncatednanalogue, [1 23]-Drs B2, that was virtually inactive on bacteria despite retaining the cationic charge ofnthe full-length peptide. Both peptides were tested on living cells using membrane permeabilization assaysnand on large unilamellar and multilamellar phospholipid vesicles composed of binary lipid mixtures byndye leakage assay, fluorescence spectroscopy, circular dichroism, and differential scanning calorimetrynand also on SDS micelles using NMR spectroscopy. The results indicate that Drs B2 induces a strongnperturbation of anionic lipid bilayers, resides at the hydrocarbon core water interface, parallel to thenplane of the membrane, and interacts preferentially with the polar head groups and glycerol backbonenregion of the anionic phospholipids, as well as the region of the lipid acyl chain near the bilayer surface.nThe interfacial location of Drs B2 induces a positive curvature of the bilayer and clustering of anionicnlipids, consistent with a carpet mechanism, that may lead to the formation of mixed peptide phospholipidntoroidal, transient pores and membrane permeation/disruption once a threshold peptide accumulation isnreached. In constrast, the truncated [1 23]-Drs B2 analogue interacts at the head group level withoutnpenetrating and perturbing the hydrophobic core of the bilayer. NMR study in SDS micelles showed thatn[1 23]-Drs B2 adopts a well-defined helix encompassing residues 2 20, whereas Drs B2 was previouslynfound to adopt helical structures interrupted around the Valn9n-Gly10nsegment. Thus the antibacterial activitynof Drs B2 depends markedly on a threshold number of hydrophobic residues to be present on bothnextremities of the helix. In a membrane environment with a strong positive curvature strain, Drs B2 cannadopt a flexible helix hinge helix structure that facilitates the concomitant insertion of the stronglynhydrophobic N- and C-termini of the peptide into the acyl core of the membrane.
机译：Dermaseptin B2（Drs B2）是33个残基长的阳离子，螺旋螺旋抗菌肽，具有针对多种微生物（包括细菌，酵母，真菌和原生动物）的膜破坏活性，但其确切的作用机理仍然不佳。定义。与C端截短的类似物[1 23] -Drs B2比较，对Drs B2的肽膜相互作用进行了详细的表征，尽管它保留了全长肽的阳离子电荷，但实际上对细菌没有活性。两种肽均通过膜透化测定法在活细胞上进行了测试，并且在双元脂质混合物组成的大单层和多层磷脂囊泡上进行了渗漏分析，荧光光谱，圆二色性和差示扫描量热法，并在SDS胶束上使用NMR光谱法进行了测试。结果表明Drs B2引起阴离子脂质双层的强烈扰动，驻留在与膜平面平行的烃核水界面上，并优先与阴离子磷脂的极性头基和甘油主链区域以及该区域相互作用n Drs B2的界面位置引起双层的正曲率和阴离子脂质的聚集，这与地毯的机理一致，这可能导致形成混合的肽磷脂-类固醇，短暂的孔和膜渗透一旦达到阈值肽积聚，就中断/中断。相反，截短的[1 23] -Drs B2类似物在头基团水平上相互作用而不会穿透和干扰双层的疏水核。在SDS胶束中进行的NMR研究表明，n [1 23] -Drs B2采用了定义良好的螺旋，包含残基2 20，而Drs B2先前被发现采用了在Valn9n-Gly10nsegment周围中断的螺旋结构。因此，Drs B2的抗菌活性明显取决于在螺旋的两个末端上都存在的疏水残基的阈值数量。在具有强正曲率应变的膜环境中，Drs B2可以采用灵活的螺旋铰链螺旋结构，该结构有助于将肽的强疏水性N-和C-末端同时插入到膜的酰基核中。

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