DOPC与DOPE作为基因治疗的辅助脂质：使用DLin-MC3-DMA的分子动力学模拟,Physical Chemistry Chemical Physics

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DOPC与DOPE作为基因治疗的辅助脂质：使用DLin-MC3-DMA的分子动力学模拟
Physical Chemistry Chemical Physics ( IF 2.9 ) Pub Date : 2020-12-9 , DOI: 10.1039/d0cp05111j
Inna Ermilova _{1,

2,

3,

4} , Jan Swenson _{1,

2,

3,

4}

Affiliation

可电离的脂质是现代治疗性脂质纳米颗粒（LNP）的重要化合物。DLin-MC3-DMA是最有前途的可离子化脂质（或胺类脂质）之一。根据其药物用途，这些LNP还可以包含各种辅助脂质，例如磷酸化和聚乙二醇化的脂质，胆固醇和核酸。由于其复杂的组成，这些治疗剂的结构尚未得到适当的改进。因此，尚未确定每种脂质在LNPs药理特性中的作用。在这项工作中，得出了DLin-MC3-DMA中性形式的原子模型，并进行了全原子分子动力学（MD）模拟，以研究磷脂首基对壳膜可能性质的影响。 LNP。构造了包含两种不同比例的DLin-MC3-DMA（5摩尔％和15摩尔％）的DOPC或DOPE脂质的双层，并在中性pH 7.4下进行了模拟。MD轨迹分析的结果表明，DOPE脂质头基团与DLin-MC3-DMA的脂质尾部和羰基氧密切相关，而对于DOPC脂质头基团则未观察到显着关联。此外，DOPE和DLin-MC3-DMA之间的强关联导致DLin-MC3-DMA定位在膜表面。脂质之间的这种相互作用减慢了所有模拟双层的横向扩散，在带有DOPE的膜中观察到扩散速率的更大幅度降低。这可以解释脂质双层与磷脂酰乙醇胺的低水渗透性，可能

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DOPC versus DOPE as a helper lipid for gene-therapies: molecular dynamics simulations with DLin-MC3-DMA

Ionizable lipids are important compounds of modern therapeutic lipid nano-particles (LNPs). One of the most promising ionizable lipids (or amine lipids) is DLin-MC3-DMA. Depending on their pharmaceutical application these LNPs can also contain various helper lipids, such as phospho- and pegylated lipids, cholesterol and nucleic acids as a cargo. Due to their complex compositions the structures of these therapeutics have not been refined properly. Therefore, the role of each lipid in the pharmacological properties of LNPs has not been determined. In this work an atomistic model for the neutral form of DLin-MC3-DMA was derived and all-atom molecular dynamics (MD) simulations were carried out in order to investigate the effect of the phospholipid headgroup on the possible properties of the shell-membranes of LNPs. Bilayers containing either DOPC or DOPE lipids at two different ratios of DLin-MC3-DMA (5 mol% and 15 mol%) were constructed and simulated at neutral pH 7.4. The results from the analysis of MD trajectories revealed that DOPE lipid headgroups associated strongly with lipid tails and carbonyl oxygens of DLin-MC3-DMA, while for DOPC lipid headgroups no significant associations were observed. Furthermore, the strong associations between DOPE and DLin-MC3-DMA result in the positioning of DLin-MC3-DMA at the surface of the membrane. Such an interplay between the lipids slows down the lateral diffusion of all simulated bilayers, where a more dramatic decrease of the diffusion rate is observed in membranes with DOPE. This can explain the low water penetration of lipid bilayers with phosphatidylethanolamines and, probably, can relate to the bad transfection properties of LNPs with DOPE and DLin-MC3-DMA.

更新日期：2020-12-09

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