Structural insights on ionizable Dlin-MC3-DMA lipids in DOPC layers by combining accurate atomistic force fields, molecular dynamics simulations and neutron reflectivity,Nanoscale

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Structural insights on ionizable Dlin-MC3-DMA lipids in DOPC layers by combining accurate atomistic force fields, molecular dynamics simulations and neutron reflectivity
Nanoscale ( IF 5.8 ) Pub Date : 2023-06-22 , DOI: 10.1039/d3nr00987d
Mohd Ibrahim ₁ , Jennifer Gilbert _{2,

3} , Marcel Heinz ₁ , Tommy Nylander _{2,

3,

4,

5} , Nadine Schwierz _{1,

6}

Affiliation

Ionizable lipids such as the promising Dlin-MC3-DMA (MC3) are essential for the successful design of lipid nanoparticles (LNPs) as drug delivery agents. Combining molecular dynamics simulations with experimental data, such as neutron reflectivity experiments and other scattering techniques, is essential to provide insights into the internal structure of LNPs, which is not fully understood to date. However, the accuracy of the simulations relies on the choice of force field parameters and high-quality experimental data is indispensable to verify the parametrization. For MC3, different parameterizations in combination with the CHARMM and the Slipids force fields have recently emerged. Here, we complement the existing efforts by providing parameters for cationic and neutral MC3 compatible with the AMBER Lipid17 force field. Subsequently, we carefully assess the accuracy of the different force fields by providing a direct comparison to neutron reflectivity experiments of mixed lipid bilayers consisting of MC3 and DOPC at different pHs. At low pH (cationic MC3) and at high pH (neutral MC3) the newly developed MC3 parameters in combination with AMBER Lipid17 for DOPC give good agreement with the experiments. Overall, the agreement is similar compared to the Park-Im parameters for MC3 in combination with the CHARMM36 force field for DOPC. The Ermilova–Swenson MC3 parameters in combination with the Slipids force field underestimate the bilayer thickness. While the distribution of cationic MC3 is very similar, the different force fields for neutral MC3 reveal distinct differences ranging from strong accumulation in the membrane center (current MC3/AMBER Lipid17 DOPC), over mild accumulation (Park-Im MC3/CHARMM36 DOPC) to surface accumulation (Ermilova-Swenson MC3/Slipids DOPC). These pronounced differences highlight the importance of accurate force field parameters and their experimental validation.

中文翻译：

通过结合精确的原子力场、分子动力学模拟和中子反射率，深入了解 DOPC 层中可电离的 Dlin-MC3-DMA 脂质的结构

可电离的脂质，例如有前景的 Dlin-MC3-DMA (MC3)，对于成功设计作为药物递送剂的脂质纳米颗粒 (LNP) 至关重要。将分子动力学模拟与实验数据（例如中子反射率实验和其他散射技术）相结合对于深入了解 LNP 的内部结构至关重要，而迄今为止尚未完全了解 LNP 的内部结构。然而，模拟的准确性取决于力场参数的选择，高质量的实验数据对于验证参数化是必不可少的。对于 MC3，最近出现了与 CHARMM 和 Slipids 力场相结合的不同参数化。在这里，我们通过提供与 AMBER Lipid17 力场兼容的阳离子和中性 MC3 参数来补充现有的工作。随后，我们通过与由 MC3 和 DOPC 组成的混合脂质双层在不同 pH 值下的中子反射率实验进行直接比较，仔细评估了不同力场的准确性。在低 pH（阳离子 MC3）和高 pH（中性 MC3）下，新开发的 MC3 参数与用于 DOPC 的 AMBER Lipid17 相结合，与实验具有良好的一致性。总体而言，与 MC3 的 Park-Im 参数结合 DOPC 的 CHARMM36 力场相比，该协议相似。Ermilova-Swenson MC3 参数与 Slipids 力场相结合低估了双层厚度。虽然阳离子 MC3 的分布非常相似，但中性 MC3 的不同力场揭示了明显的差异，包括在膜中心的强烈积累（当前的 MC3/AMBER Lipid17 DOPC），从轻度积累（Park-Im MC3/CHARMM36 DOPC）到表面积累（Ermilova-Swenson MC3/Slipids DOPC）。这些明显的差异凸显了精确的力场参数及其实验验证的重要性。

更新日期：2023-06-22

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