Ermilova Inna, Swenson Jan
Department of Physics, Chalmers University of Technology, Gothenburg, Sweden.
Phys Chem Chem Phys. 2020 Dec 23;22(48):28256-28268. doi: 10.1039/d0cp05111j.
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.
可电离脂质是现代治疗性脂质纳米颗粒（LNP）的重要组成部分。最有前景的可电离脂质（或胺脂质）之一是DLin-MC3-DMA。根据其药物应用，这些LNP还可包含各种辅助脂质，如磷酸化和聚乙二醇化脂质、胆固醇以及作为载药的核酸。由于其组成复杂，这些治疗剂的结构尚未得到恰当完善。因此，每种脂质在LNP药理特性中的作用尚未确定。在这项工作中，推导了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，以研究磷脂头部基团对LNP壳膜可能特性的影响。构建了含有不同比例（5摩尔%和15摩尔%）DLin-MC3-DMA的二油酰磷脂酰胆碱（DOPC）或二油酰磷脂酰乙醇胺（DOPE）脂质双层，并在中性pH 7.4条件下进行模拟。MD轨迹分析结果表明，DOPE脂质头部基团与DLin-MC3-DMA的脂质尾部和羰基氧强烈缔合，而对于DOPC脂质头部基团则未观察到明显缔合。此外，DOPE与DLin-MC3-DMA之间的强缔合导致DLin-MC3-DMA定位在膜表面。脂质之间的这种相互作用减缓了所有模拟双层的横向扩散，其中在含有DOPE的膜中观察到扩散速率有更显著的降低。这可以解释含有磷脂酰乙醇胺的脂质双层的低水渗透性，并且可能与含有DOPE和DLin-MC3-DMA的LNP的不良转染特性有关。
