Characterization of a potent antimicrobial lipopeptide via coarse-grained molecular dynamics.
Characterization of a potent antimicrobial lipopeptide via coarse-grained molecular dynamics.
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DOI：
10.1016/j.bbamem.2011.07.025
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发表时间：
2012-02
影响因子：
3.4
通讯作者：
Grossfield, Alan
中科院分区：
文献类型：
--
作者：
Horn, Joshua N.;Sengillo, Jesse D.;Lin, Dejun;Romo, Tod D.;Grossfield, Alan
抗生素耐药病原体的流行是一个主要的医学问题，促使人们对开发新型抗菌化合物产生越来越大的兴趣。一组这样的自然产生的化合物，被称为抗菌肽(AMPs)，具有广谱活性，但在临床使用方面有许多限制。最近的工作已经导致了一系列具有微摩尔最低抑制浓度和良好的细菌膜选择性的抗菌脂肽(AMLP)。为了表征一种有效的合成脂肽C16-KGGK，我们使用了马提尼力场的多微秒粗粒度模拟，总模拟时间接近46微秒。这些模拟显示C16-KGGK快速结合，在溶液中形成胶束，以模拟细菌脂双层。此外，当结合到双层表面时，这些脂肽通过将带负电荷的POPG脂类招募到结合部位来改变局部脂质组织。这种双分子层的剧烈重组很可能对依赖于特定双分子层组成的双分子层动力学和细胞过程产生重大影响。相比之下，模拟显示脂肽和模型哺乳动物双层之间没有关联。这些模拟提供了对脂肽选择性的生物物理见解，并提出了一种可能的抗菌作用机制。
The prevalence of antibiotic-resistant pathogens is a major medical concern, prompting increased interest in the development of novel antimicrobial compounds. One such set of naturally occurring compounds, known as antimicrobial peptides (AMPs), have broad-spectrum activity, but come with many limitations for clinical use. Recent work has resulted in a set of antimicrobial lipopeptides (AMLPs) with micromolar minimum inhibitory concentrations and excellent selectivity for bacterial membranes. To characterize a potent, synthetic lipopeptide, C16-KGGK, we used multi-microsecond coarse-grained simulations with the MARTINI forcefield, with a total simulation time of nearly 46 microseconds. These simulations show rapid binding of C16-KGGK, which forms micelles in solution, to model bacterial lipid bilayers. Furthermore, upon binding to the surface of the bilayer, these lipopeptides alter the local lipid organization by recruiting negatively charged POPG lipids to the site of binding. It is likely that this drastic reorganization of the bilayer has major effects on bilayer dynamics and cellular processes that depend on specific bilayer compositions. By contrast, the simulations revealed no association between the lipopeptides and model mammalian bilayers. These simulations provide biophysical insights into lipopeptide selectivity and suggest a possible mechanism for antimicrobial action.
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