Department of Physics and Astronomy, University of Waterloo, Waterloo, Ontario N2L 3G1, Canada.
Phys Rev E. 2017 Oct;96(4-1):042405. doi: 10.1103/PhysRevE.96.042405. Epub 2017 Oct 9.
The permeability of the bacterial outer membrane, enclosing Gram-negative bacteria, depends on the interactions of the outer, lipopolysaccharide (LPS) layer, with surrounding ions and molecules. We present a coarse-grained model for describing how cationic amphiphilic molecules (e.g., antimicrobial peptides) interact with and perturb the LPS layer in a biologically relevant medium, containing monovalent and divalent salt ions (e.g., Mg^{2+}). In our approach, peptide binding is driven by electrostatic and hydrophobic interactions and is assumed to expand the LPS layer, eventually priming it for disruption. Our results suggest that in parameter ranges of biological relevance (e.g., at micromolar concentrations) the antimicrobial peptide magainin 2 effectively disrupts the LPS layer, even though it has to compete with Mg^{2+} for the layer. They also show how the integrity of LPS is restored with an increasing concentration of Mg^{2+}. Using the approach, we make a number of predictions relevant for optimizing peptide parameters against Gram-negative bacteria and for understanding bacterial strategies to develop resistance against cationic peptides.
细菌外膜的通透性取决于革兰氏阴性细菌的外层、脂多糖 (LPS) 层与周围离子和分子的相互作用。我们提出了一种粗粒度模型来描述阳离子两亲分子（例如，抗菌肽）如何在含有单价和二价盐离子（例如，Mg^{2+}）的生物相关介质中与 LPS 层相互作用并扰乱 LPS 层。在我们的方法中，肽结合是由静电和疏水相互作用驱动的，并假定它会扩展 LPS 层，最终使其易于破坏。我们的结果表明，在生物学相关的参数范围内（例如，在微摩尔浓度下），抗菌肽magainin 2 有效地破坏了 LPS 层，尽管它必须与 Mg^{2+}竞争该层。它们还显示了 LPS 的完整性如何随着 Mg^{2+}浓度的增加而恢复。我们使用该方法对革兰氏阴性菌的抗菌肽参数进行了优化，并对细菌对抗阳离子肽产生耐药性的策略进行了理解，提出了一些相关的预测。
