Ligand Lipophilicity Determines Molecular Mechanisms of Nanoparticle Adsorption to Lipid Bilayers
Ligand Lipophilicity Determines Molecular Mechanisms of Nanoparticle Adsorption to Lipid Bilayers
复制标题
DOI：
10.1021/acsnano.3c11854
复制
发表时间：
2024-02-14
期刊：
影响因子：
17.1
通讯作者：
Van Lehn，Reid C.
中科院分区：
文献类型：
--
作者：
Huang-Zhu，Carlos A.;Sheavly，Jonathan K.;Van Lehn，Reid C.
配体功能化纳米颗粒与细胞膜的相互作用影响细胞摄取、细胞毒性和相关行为，但将这些相互作用与配体性质联系起来仍然具有挑战性。在这项工作中，我们进行了粗粒度的分子动力学模拟，以研究配体功能化的阳离子金纳米颗粒（NPs）在单组分脂质双分子层（作为模型细胞膜）上的吸附如何受到配体端基亲脂性的影响。一组直径为2nm的NPs，每个NPs都涂有一层有机配体，仅在其端基上有所不同，模拟了最近实验研究的NPs。进行元动力学计算以确定吸附的自由能景观的关键特征，作为NP与双层的距离和NP -脂质接触次数的函数。这些模拟表明，由于脂质从双分子层中提取到单分子层中，NP吸附在热力学上对所有NP都是有利的。为了解决与配体相关的吸附行为差异，进行了弦法计算，以计算吸附的最小自由能途径。这些计算揭示了自由能势垒对配体端基亲脂性的非单调依赖性。由于有利的np -脂质接触仅通过不利的脂质尾部基团伸出双分子层而开始，因此预测亲脂性最低的端基具有较大的自由能垒。预测了中间亲脂性端基的最小自由能势垒，它们通过嵌入双分子层来促进np -脂质接触。出乎意料的是，最亲脂的端基也被预测为大的自由能势垒，它们仍然被隔离在配体单层内，而不是嵌入在双层内。这些趋势与过去的实验测量结果大致一致，并揭示了配体亲脂性的细微变化如何通过影响脂质与配体相互作用的相互作用来决定吸附机制和相关动力学。
The interactions of ligand-functionalized nanoparticles with the cell membrane affect cellular uptake, cytotoxicity, and related behaviors, but relating these interactions to ligand properties remains challenging. In this work, we perform coarse-grained molecular dynamics simulations to study how the adsorption of ligand-functionalized cationic gold nanoparticles (NPs) to a single-component lipid bilayer (as a model cell membrane) is influenced by ligand end group lipophilicity. A set of 2 nm diameter NPs, each coated with a monolayer of organic ligands that differ only in their end groups, was simulated to mimic NPs recently studied experimentally. Metadynamics calculations were performed to determine key features of the free energy landscape for adsorption as a function of the distance of the NP from the bilayer and the number of NP–lipid contacts. These simulations revealed that NP adsorption is thermodynamically favorable for all NPs due to the extraction of lipids from the bilayer and into the NP monolayer. To resolve ligand-dependent differences in adsorption behavior, string method calculations were performed to compute minimum free energy pathways for adsorption. These calculations revealed a surprising nonmonotonic dependence of the free energy barrier for adsorption on ligand end group lipophilicity. Large free energy barriers are predicted for the least lipophilic end groups because favorable NP–lipid contacts are initiated only through the unfavorable protrusion of lipid tail groups out of the bilayer. The smallest free energy barriers are predicted for end groups of intermediate lipophilicity which promote NP–lipid contacts by intercalating within the bilayer. Unexpectedly, large free energy barriers are also predicted for the most lipophilic end groups which remain sequestered within the ligand monolayer rather than intercalating within the bilayer. These trends are broadly in agreement with past experimental measurements and reveal how subtle variations in ligand lipophilicity dictate adsorption mechanisms and associated kinetics by influencing the interplay of lipid–ligand interactions.