The efficacies of modern gene-therapies strongly depend on their contents. At the same time the most potent formulations might not contain the best compounds. In this work we investigated the effect of phospholipids and their saturation on the binding ability of (6Z,9Z,28Z,31Z)-heptatriacont-6,9,28,31-tetraene-19-yl 4-(dimethylamino) butanoate (DLin-MC3-DMA) to model membranes at the neutral pH. We discovered that DLin-MC3-DMA has affinity to the most saturated monocomponent lipid bilayer 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and an aversion to the unsaturated one 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC). The preference to a certain membrane was also well-correlated to the phase transition temperatures of phospholipid bilayers, and to their structural and dynamical properties. Additionally, in the case of the presence of DLin-MC3-DMA in the membrane with DOPC the ionizable lipid penetrated it, which indicates possible synergistic effects. Comparisons with other ionizable lipids were performed using a model lipid bilayer of 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC). Particularly, the lipids heptadecan-9-yl 8-[2-hydroxyethyl-(6-oxo-6-undecoxyhexyl)amino]octanoate (SM-102) and [(4-hydroxybutyl) azanediyl] di(hexane-6,1-diyl) bis(2-hexyldecanoate) (ALC-0315) from modern mRNA-vaccines against COVID-19 were investigated and force fields parameters were derived for those new lipids. It was discovered that ALC-0315 binds strongest to the membrane, while DLin-MC3-DMA is not able to reside in the bilayer center. The ability to penetrate the membrane POPC by SM-102 and ALC-0315 can be related to their saturation, comparing to DLin-MC3-DMA.

现代基因疗法的功效在很大程度上取决于它们的内容。同时，最有效的配方可能不包含最好的化合物。在这项工作中，我们研究了磷脂及其饱和度对 (6 Z ,9 Z ,28 Z ,31 Z )-heptatriacont-6,9,28,31-tetraene-19-yl 4-(dimethylamino)结合能力的影响) 丁酸盐 (DLin-MC3-DMA) 在中性 pH 值下模拟膜。我们发现 DLin-MC3-DMA 对饱和度最高的单组分脂质双层 1,2-dimyristoyl- sn -glycero-3-phosphocholine (DMPC) 具有亲和力，并且厌恶不饱和的 1,2-dioleoyl- sn-甘油 3-磷酸胆碱 (DOPC)。对某种膜的偏好也与磷脂双层的相变温度及其结构和动力学特性密切相关。此外，如果膜中存在 DLin-MC3-DMA 和 DOPC，可电离脂质会渗透它，这表明可能存在协同效应。使用 1-棕榈酰-2-油酰-甘油-3-磷酸胆碱 (POPC) 模型脂质双层与其他可电离脂质进行比较。特别是，脂质 heptadecan-9-yl 8-[2-hydroxyethyl-(6-oxo-6-undecoxyhexyl)amino]octanoate (SM-102) 和 [(4-hydroxybutyl) azanediyl] di(hexane-6,1-二基）双（2-己基癸酸酯）（ALC-0315）来自现代 mRNA 疫苗对 COVID-19 进行了研究，并推导出了这些新脂质的力场参数。发现 ALC-0315 与膜的结合最强，而 DLin-MC3-DMA 不能位于双层中心。与 DLin-MC3-DMA 相比，SM-102 和 ALC-0315 穿透膜 POPC 的能力可能与其饱和度有关。