Atomistic Scale Effects of Lipopolysaccharide Modifications on Bacterial Outer Membrane Defenses.
Atomistic Scale Effects of Lipopolysaccharide Modifications on Bacterial Outer Membrane Defenses.
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DOI：
10.1016/j.bpj.2018.02.006
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发表时间：
2018-03
影响因子：
3.4
通讯作者：
Amy M Rice;Jeff Wereszczynski
中科院分区：
文献类型：
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作者：
Amy M Rice;Jeff Wereszczynski
脂多糖（Lipopolysaccharides，LPS）是革兰氏阴性菌外膜的主要组成成分，沙门氏菌与其他细菌一样，能够通过PhoPQ途径对LPS分子进行化学修饰，从而抵抗宿主的免疫应答。这些修饰使外膜对抗菌肽（AMP），大的亲脂性药物和阳离子耗尽更具抗性，并且对于宿主生物体内的生存至关重要。据信，这些LPS修饰通过加强相邻LPS分子之间的横向相互作用来防止大分子和AMP的渗透。在这里，我们进行了一系列长时间尺度的分子动力学模拟，以研究三个关键的S. entericlavid A修饰如何影响双层性质，重点是膜结构特征，横向相互作用和二价阳离子桥接网络。我们的研究结果辨别了每种修饰通过增加氢键和更紧密的脂质堆积等效应对加强细菌外膜的独特影响。此外，所研究的修饰之一将Ca 2+从脂质A区域转移，取代其作为相邻脂质之间的主要交联剂，并可能使细菌对竞争性取代膜表面阳离子的AMP不太敏感。这些结果进一步提高了我们对外膜化学性质的理解，并有助于阐明外膜修饰系统（如肠道沙门氏菌中的PhoPQ）如何能够改变细菌的毒力。
Lipopolysaccharides (LPS) are a main constituent of the outer membrane of Gram-negative bacteria.Salmonella enterica, like many other bacterial species, are able to chemically modify the structure of their LPS molecules through the PhoPQ pathway as a defense mechanism against the host immune response. These modifications make the outer membrane more resistant to antimicrobial peptides (AMPs), large lipophilic drugs, and cation depletion, and are crucial for survival within a host organism. It is believed that these LPS modifications prevent the penetration of large molecules and AMPs through a strengthening of lateral interactions between neighboring LPS molecules. Here, we performed a series of long-timescale molecular dynamics simulations to study how each of three keyS. entericalipid A modifications affect bilayer properties, with a focus on membrane structural characteristics, lateral interactions, and the divalent cation bridging network. Our results discern the unique impact each modification has on strengthening the bacterial outer membrane through effects such as increased hydrogen bonding and tighter lipid packing. Additionally, one of the modifications studied shifts Ca2+from the lipid A region, replacing it as a major cross-linking agent between adjacent lipids and potentially making bacteria less susceptible to AMPs that competitively displace cations from the membrane surface. These results further improve our understanding of outer membrane chemical properties and help elucidate how outer membrane modification systems, such as PhoPQ inS. enterica, are able to alter bacterial virulence.