Molecular Dynamics Simulation and Experimental Studies of Gold Nanoparticle Templated HDL-like Nanoparticles for Cholesterol Metabolism Therapeutics
Molecular Dynamics Simulation and Experimental Studies of Gold Nanoparticle Templated HDL-like Nanoparticles for Cholesterol Metabolism Therapeutics
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DOI：
10.1021/acsami.6b12249
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发表时间：
2017-01-18
影响因子：
9.5
通讯作者：
Schatz, George C.
中科院分区：
文献类型：
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作者：
Lai, Cheng-Tsung;Sun, Wangqiang;Schatz, George C.
高密度脂蛋白（HDL）在胆固醇的转运和代谢中起着重要作用。 HDL 模拟物正在被探索作为潜在的强大治疗剂，用于去除动脉斑块中过量的胆固醇。用载脂蛋白 A-I 和脂质 1,2-二棕榈酰-sn-甘油-3-磷酸胆碱和 1,2-二棕榈酰-sn-甘油-3-磷酸乙醇胺-N-[3-(2-吡啶基二硫代)丙酸酯] 功能化的金纳米颗粒 (AuNP) 已被证明是细胞胆固醇的强大受体。然而，关于这种功能化 HDL AuNP 的详细结构信息仍然缺乏。在这项研究中，我们使用 X 射线光电子能谱和卵磷脂/胆固醇酰基转移酶激活实验以及粗粒度和全原子分子动力学模拟来模拟 HDL AuNP 构造的结构和胆固醇摄取特性。通过模拟不同的负载载脂蛋白的 AuNP，我们发现在有和没有 apoA-I 的区域中脂质的取向不同。我们还表明，在这种功能化 HDL AuNP 中，胆固醇酯的分布保持着与天然 HDL 中发现的梯度类似的反向浓度梯度。
High-density lipoprotein (HDL) plays an important role in the transport and metabolism of cholesterol. Mimics of HDL are being explored as potentially powerful therapeutic agents for removing excess cholesterol from arterial plaques. Gold nanoparticles (AuNPs) functionalized with apolipoprotein A-I and with the lipids 1,2-dipalmitoyl-sn-glycero-3-phosphocholine and 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-[3-(2-pyridyldithio)propionate] have been demonstrated to be robust acceptors of cellular cholesterol. However, detailed structural information about this functionalized HDL AuNP is still lacking. In this study, we have used X-ray photoelectron spectroscopy and lecithin/cholesterol acyltransferase activation experiments together with coarse-grained and all-atom molecular dynamics simulations to model the structure and cholesterol uptake properties of the HDL AuNP construct. By simulating different apolipoprotein-loaded AuNPs, we find that lipids are oriented differently in regions with and without apoA-I. We also show that in this functionalized HDL AuNP, the distribution of cholesteryl ester maintains a reverse concentration gradient that is similar to the gradient found in native HDL.