Interaction of the antimicrobial peptide polymyxin B1 with both membranes of E. coli: a molecular dynamics study.
Interaction of the antimicrobial peptide polymyxin B1 with both membranes of E. coli: a molecular dynamics study.
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DOI：
10.1371/journal.pcbi.1004180
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发表时间：
2015-04
影响因子：
4.3
通讯作者：
Khalid S
中科院分区：
文献类型：
--
作者：
Berglund NA;Piggot TJ;Jefferies D;Sessions RB;Bond PJ;Khalid S
抗菌肽是小的阳离子蛋白质，可以通过与细菌细胞膜的相互作用诱导细菌细胞裂解。已经提出了不同的细胞裂解机制，但这些模型往往忽略了膜的化学组成的作用，这在细菌物种之间是不同的，甚至在单个细胞内也是异质的。革兰氏阴性菌如E.大肠杆菌含有两种成分不同的膜。为此，我们首次报道了抗菌肽多粘菌素B1与大肠杆菌内外膜复杂模型相互作用的分子动力学模拟研究。杆菌>16微秒的模拟结果预测，多粘菌素B1可能通过不同的机制与膜相互作用。脂肽聚集在外膜的脂多糖头基区域，插入脂质A尾内的趋势有限。相反，脂肽容易插入内膜核心，并且伴随的水合作用增加可能是双层不稳定和抗菌功能的原因。鉴于迫切需要开发新的，有效的抗生素，这里提出的结果揭示了关键的机制细节，可用于未来的合理药物开发。抗菌肽具有通过与细菌膜相互作用杀死有害细菌的能力。这份手稿描述了第一次报道的计算研究抗菌肽与革兰氏阴性细菌的两种膜的相互作用。虽然抗微生物肽已经成为许多模拟研究的主题，但这些研究没有纳入天然膜的生物化学异质性。我们的模拟增加了缺失的生化细节，并在这样做，揭示了多粘菌素B1与E.大肠杆菌，其实是不同的。这些肽很容易插入内膜，而与含有LPS的外膜的相互作用则更为复杂。总之，我们的研究结果代表了未来针对这些细菌的药物开发的关键发现。
Antimicrobial peptides are small, cationic proteins that can induce lysis of bacterial cells through interaction with their membranes. Different mechanisms for cell lysis have been proposed, but these models tend to neglect the role of the chemical composition of the membrane, which differs between bacterial species and can be heterogeneous even within a single cell. Moreover, the cell envelope of Gram-negative bacteria such as E. coli contains two membranes with differing compositions. To this end, we report the first molecular dynamics simulation study of the interaction of the antimicrobial peptide, polymyxin B1 with complex models of both the inner and outer membranes of E. coli. The results of >16 microseconds of simulation predict that polymyxin B1 is likely to interact with the membranes via distinct mechanisms. The lipopeptides aggregate in the lipopolysaccharide headgroup region of the outer membrane with limited tendency for insertion within the lipid A tails. In contrast, the lipopeptides readily insert into the inner membrane core, and the concomitant increased hydration may be responsible for bilayer destabilization and antimicrobial function. Given the urgent need to develop novel, potent antibiotics, the results presented here reveal key mechanistic details that may be exploited for future rational drug development. Antimicrobial peptides have the ability to kill harmful bacteria through interaction with bacterial membranes. This manuscript describes the first reported computational study of antimicrobial peptide interaction with both membranes of a Gram-negative bacterium. While antimicrobial peptides have been the topic of many simulation studies, these studies have not incorporated the biochemical heterogeneity of natural membranes. Our simulations add the missing biochemical details and in doing so, reveal that the mechanisms of interaction of polymyxin B1 with the inner and outer membranes of E. coli, are really rather different. The peptides insert readily into the inner membrane, whereas the interaction with the LPS-containing outer membrane is more complex. In summary our results represent a key finding for future drug development that targets these bacteria.
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