All-Atom Molecular Dynamics-Based Analysis of Membrane-Stabilizing Copolymer Interactions with Lipid Bilayers Probed under Constant Surface Tensions
All-Atom Molecular Dynamics-Based Analysis of Membrane-Stabilizing Copolymer Interactions with Lipid Bilayers Probed under Constant Surface Tensions
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DOI：
10.1021/acs.jpcb.7b08938
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发表时间：
2017-11-30
影响因子：
3.3
通讯作者：
Metzger, Joseph M.
中科院分区：
文献类型：
--
作者：
Houang, Evelyne M.;Bates, Frank S.;Metzger, Joseph M.
建立了一个适用于分子动力学研究的全原子磷脂双层和三嵌段共聚物模型。进行这些以研究在施加侧向表面张力（γ）以模拟膜机械应力下膜稳定三嵌段共聚物P188与1-棕榈酰-2-油酰-sn-甘油-3-磷脂酰胆碱（POPC）脂质双层之间的相互作用机制。结果表明，P188的插入是由疏水性聚环氧丙烷（PPO）核心驱动的，并且取决于每个脂质的双层面积。此外，P188的插入增加了双层对机械破裂的抵抗力，正如破坏双层所需的绝对侧向压力显着增加所观察到的那样。为了进一步研究P188潜在的膜稳定剂功能的具体化学特征，用与P188相同类别但具有不同化学组成和尺寸的三嵌段共聚物进行了一系列MD模拟。结果表明，三嵌段共聚物插入到脂质双层是依赖于整体共聚物的疏水性，与较高的共聚物疏水性需要减少双层面积/脂质插入比。进一步的分析表明，共聚物插入对膜机械完整性的影响也取决于疏水性。此处，P188插入显著增加了使POPC双层破裂所需的绝对表观侧向压力，从而保护膜免受机械应力。与此形成鲜明对比的是，高度疏水的共聚物降低了膜破裂所需的侧向压力，从而使膜明显更容易受到机械应力的影响。这些新的计算机研究结果与最近使用合成脂质双层和体外肌肉细胞以及体内小鼠模型的实验结果一致。总的来说，这些数据强调了PEO-PPO-PEO共聚物化学组成在体外和体内基于共聚物的肌膜稳定中的重要性。分子动力学模拟的全原子模型研究具有增强的膜相互作用性能的新型共聚物的承诺。
An all-atom phospholipid bilayer and triblock copolymer model was developed for molecular dynamics (MD) studies. These were performed to investigate the mechanism of interaction between membrane-stabilizing triblock copolymer P188 and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine (POPC) lipid bilayers under applied lateral surface tension (gamma) to model membrane mechanical stress. Results showed that P188 insertion is driven by the hydrophobic poly(propylene oxide) (PPO) core and dependent on bilayer area per lipid. Moreover, insertion of P188 increased the bilayer's resistance to mechanical rupture, as observed by a significant increase in the absolute lateral pressure required to disrupt the bilayer. To further investigate the specific chemical features of P188 underlying membrane stabilizer function, a series of MD simulations with triblock copolymers of the same class as P188 but of varying chemical composition and sizes were performed. Results showed that triblock copolymer insertion into the lipid bilayer is dependent on overall copolymer hydrophobicity, with higher copolymer hydrophobicity requiring a reduced bilayer area per lipid ratio for insertion. Further analysis revealed that the effect of copolymer insertion on membrane mechanical integrity was also dependent on hydrophobicity. Here, P188 insertion significantly increased the absolute apparent lateral pressure required to rupture the POPC bilayer, thereby protecting the membrane against mechanical stress. In marked contrast, highly hydrophobic copolymers decreased the lateral pressure necessary for membrane rupture and thus rendering the membrane significantly more susceptible to mechanical stress. These new in silico findings align with recent experimental findings using synthetic lipid bilayers and in muscle cells in vitro and mouse models in vivo. Collectively, these data underscore the importance of PEO-PPO-PEO copolymer chemical composition in copolymer-based muscle membrane stabilization in vitro and in vivo. All-atom modeling with MD simulations holds promise for investigating novel copolymers with enhanced membrane interacting properties.