PDF(Pubmed)
Abstract：
Capitellacin is the β-hairpin membrane-active cationic antimicrobial peptide from the marine polychaeta Capitella teleta. Capitellacin exhibits antibacterial activity, including against drug-resistant strains. To gain insight into the mechanism of capitellacin action, we investigated the structure of the peptide in the membrane-mimicking environment of dodecylphosphocholine (DPC) micelles using high-resolution NMR spectroscopy. In DPC solution, two structural forms of capitellacin were observed: a monomeric β-hairpin was in equilibrium with a dimer formed by the antiparallel association of the N-terminal β-strands and stabilized by intermonomer hydrogen bonds and Van der Waals interactions. The thermodynamics of the enthalpy-driven dimerization process was studied by varying the temperature and molar ratios of the peptide to detergent. Cooling the peptide/detergent system promoted capitellacin dimerization. Paramagnetic relaxation enhancement induced by lipid-soluble 12-doxylstearate showed that monomeric and dimeric capitellacin interacted with the surface of the micelle and did not penetrate into the micelle interior, which is consistent with the \"carpet\" mode of membrane activity. An analysis of the known structures of β-hairpin AMP dimers showed that their dimerization in a membrane-like environment occurs through the association of polar or weakly hydrophobic surfaces. A comparative analysis of the physicochemical properties of β-hairpin AMPs revealed that dimer stability and hemolytic activity are positively correlated with surface hydrophobicity. An additional positive correlation was observed between hemolytic activity and AMP charge. The data obtained allowed for the provision of a more accurate description of the mechanism of the oligomerization of β-structural peptides in biological membranes.
摘要：
Capitellacin是来自海洋多毛capitellateleta的β-发夹膜活性阳离子抗菌肽。Capitellacin表现出抗菌活性，包括抗耐药菌株。为了深入了解capitellacin的作用机制，我们使用高分辨率NMR光谱研究了十二烷基磷酸胆碱（DPC）胶束的膜模拟环境中肽的结构。在DPC解决方案中,观察到capitellacin的两种结构形式：单体β发夹与N末端β链的反平行缔合形成的二聚体平衡，并通过单体间氢键和范德华相互作用稳定。通过改变肽与洗涤剂的温度和摩尔比，研究了焓驱动的二聚过程的热力学。冷却肽/洗涤剂系统促进了capitellacin二聚化。脂溶性12-羟硬脂酸酯诱导的顺磁弛豫增强表明，单体和二聚体capitellacin与胶束表面相互作用，并且不渗透到胶束内部，这与膜活动的“地毯”模式一致。对β-发夹AMP二聚体的已知结构的分析表明，它们在膜状环境中的二聚化是通过极性或弱疏水表面的缔合而发生的。对β-发夹型AMP的理化性质的比较分析表明，二聚体稳定性和溶血活性与表面疏水性呈正相关。在溶血活性和AMP电荷之间观察到另外的正相关。获得的数据可以更准确地描述生物膜中β-结构肽的寡聚化机制。
