Role of Ionizable Lipids in SARS-CoV-2 Vaccines As Revealed by Molecular Dynamics Simulations: From Membrane Structure to Interaction with mRNA Fragments,The Journal of Physical Chemistry Letters

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Role of Ionizable Lipids in SARS-CoV-2 Vaccines As Revealed by Molecular Dynamics Simulations: From Membrane Structure to Interaction with mRNA Fragments
The Journal of Physical Chemistry Letters ( IF 4.8 ) Pub Date : 2021-11-11 , DOI: 10.1021/acs.jpclett.1c03109
Markéta Paloncýová ₁ , Petra Čechová ₁ , Martin Šrejber ₁ , Petra Kührová ₁ , Michal Otyepka _{1,

2}

Affiliation

Recent advances in RNA-based medicine have provided new opportunities for the global current challenge, i.e., the COVID-19 pandemic. Novel vaccines are based on a messenger RNA (mRNA) motif with a lipid nanoparticle (LNP) vector, consisting of high content of unique pH-sensitive ionizable lipids (ILs). Here we provide molecular insights into the role of the ILs and lipid mixtures used in current mRNA vaccines. We observed that the lipid mixtures adopted a nonlamellar organization, with ILs separating into a very disordered, pH-sensitive phase. We describe structural differences of the two ILs leading to their different congregation, with implications for the vaccine stability. Finally, as RNA interacts preferentially with IL-rich phases located at the regions with high curvature of lipid phase, local changes in RNA flexibility and base pairing are induced by lipids. A proper atomistic understanding of RNA–lipid interactions may enable rational tailoring of LNP composition for efficient RNA delivery.

中文翻译：

分子动力学模拟揭示可电离脂质在 SARS-CoV-2 疫苗中的作用：从膜结构到与 mRNA 片段的相互作用

基于 RNA 的医学的最新进展为应对当前的全球挑战（即 COVID-19 大流行）提供了新的机遇。新型疫苗基于带有脂质纳米颗粒 (LNP) 载体的信使 RNA (mRNA) 基序，由高含量的独特 pH 敏感可电离脂质 (IL) 组成。在这里，我们提供了对当前 mRNA 疫苗中使用的 IL 和脂质混合物的作用的分子见解。我们观察到脂质混合物采用非层状组织，IL 分离成非常无序的 pH 敏感相。我们描述了两种 IL 的结构差异导致其不同的聚集，并对疫苗稳定性产生影响。最后，由于 RNA 优先与位于脂质相曲率高的区域的富含 IL 的相相互作用，因此脂质会诱导 RNA 灵活性和碱基配对的局部变化。对 RNA-脂质相互作用的正确原子理解可能有助于合理调整 LNP 组成，以实现有效的 RNA 递送。

更新日期：2021-11-18

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