Cause and Effect of Melittin-Induced Pore Formation: A Computational Approach
Cause and Effect of Melittin-Induced Pore Formation: A Computational Approach
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DOI：
10.1021/la902660q
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发表时间：
2009-10-20
期刊：
影响因子：
3.9
通讯作者：
Mukhopadhyay, Chaitali
中科院分区：
文献类型：
--
作者：
Manna, Moutusi;Mukhopadhyay, Chaitali
在明确的水和离子存在下，模拟了以高肽/脂比（1:30）嵌入棕榈酰油酰磷脂酰胆碱双分子层的蜂毒素。模拟结果表明，通过结合肽的集体膜扰动，离子渗透水孔开始形成。蜂毒蛋白带正电的残基不仅起到“锚定”的作用，还会破坏细胞膜，导致细胞裂解。脂质尾序参数剖面的详细分析描述了局部膜扰动。在水腔附近的脂质采用倾斜构象，这允许局部双层变薄。由此形成的预孔可以认为是蜂毒素在双层膜中引起的结构缺陷。由于强阳离子性质，蜂毒诱导的制备孔对阴离子的选择性高于阳离子。当Cl-离子进入预孔时，它们被位于预孔壁的带正电的残基静电捕获。从计算的扩散系数来看，膜内Cl-离子的受限运动是明显的。此外，局部脂质的重新定向发生在这样一种方式，即很少的脂质头和肽螺旋可以沿着穿透水相的表面排列。脂质翻转倾向于蜂毒素诱导的环形孔而不是桶壁机制。因此，我们的结果提供了抗菌肽蜂毒素破坏膜机制的原子水平细节。
Melittin embedded in a palmitoyl oleyl phosphatidylcholine bilayer at a high peptide/lipid ratio (1:30) was simulated in the presence of explicit water and ions. The simulation results indicate the incipience of an ion-permeable water pore through collective membrane perturbation by bound peptides. The positively charged residues of melittin not only act as "anchors" but also disrupt the membrane, leading to cell lysis. A detailed analysis of the lipid tail order parameter profile depicts localized membrane perturbation. The lipids in the vicinity of the aqueous cavity adopt a tilted conformation, which allows local bilayer thinning. The prepore thus formed can be considered as the melittin-induced structural defects in the bilayer membrane. Because of the strong cationic nature, the melittin-induced prepore exhibits selectivity toward anions over cations. As Cl- ions entered into the prepore, they are electrostatically entrapped by positively charged residues located at its wall. The confined motion of the Cl- ions in the membrane interior is obvious from calculated diffusion coefficients. Moreover, reorientation of the local lipids occurs in such it way that few lipid heads along with peptide helices can line the surface of the penetrating aqueous phase. The flipping of lipids argued in favor of melittin-induced toroidal pore over a barrel-stave mechanism. Thus, our result provides atomistic level details of the mechanism of membrane disruption by antimicrobial peptide melittin.