糖基磷脂酰肌醇、药物分子和纳米粒子的跨膜机理研究

发布时间：2018-03-12 08:33

本文选题：糖基磷脂酰肌醇　切入点：药物分子　出处：《北京化工大学》2015年硕士论文　论文类型：学位论文

【摘要】：很多细胞功能,如信号传导、跨膜运输以及细胞膜融合等都需要通过各种分子和物质的跨膜来实现。近年来,通过使用计算机模拟的方法,从生物分子的大小、形状和亲疏水性质等因素着手,人们对生物分子的穿膜机理和跨膜机理进行了广泛研究,其中磷脂膜大多是由纯的饱和双链磷脂分子构成。但在实际的人体中,磷脂膜上分布着大量的跨膜蛋白、糖类或者胆固醇。这些成分都会改变着磷脂膜的性质,尤其是硬度,而目前考察膜的硬度对生物分子穿膜和跨膜的研究甚少。为了能够更加接近真实的生物膜体系,我们采用了硬度不同的膜体系来研究生物小分子的跨膜机理。本篇论文利用全原子分子动力学程序包GROMACS,对生物小分子糖基磷脂酰肌醇(GPI)、药物分子阿霉素和纳米粒子C60与不同硬度的DPPC膜(包括软的纯DPPC膜和含胆固醇的相对较硬的DPPC膜)之间的相互作用进行了系统的研究,从微观的角度探究了不同形状的生物小分子在磷脂膜中的运动状态和跨膜机理。主要的研究内容以及结论如下(1)糖基磷脂酰肌醇(GPI)是一种连接锚定蛋白和细胞膜的中介体,其分子结构主要是由糖类分子和疏水烷基链组成,生物功能是使得生物信号由细胞膜的一侧传递到另一侧,实现信号的传递,由于当糖基磷脂酰肌醇无法正常地进入到膜内时,会阻碍了某些生物性状的正确表达,从而引发疾病。论文研究表明糖基磷脂酰肌醇具有和磷脂十分类似的疏水尾链,倾向处于膜中的疏水环境。模拟的动力学过程和自由能的计算显示,在纯DPPC膜中,糖基磷脂酰肌醇无法自发进入到磷脂膜中,需要克服一定的能垒,但是它可以在很短的模拟时间内自发进入到加有胆固醇的磷脂膜中。对于GPI这种锚类小分子更倾向处于硬的磷脂区域,以便其顺利地实现锚定作用。(2)药物分子阿霉素,一种被临床广泛应用的疏水抗癌药物,但是疗效不高,主要原因是受细胞膜截留的影响,较难到达生物体的癌化位置。论文在疏水药物分子阿霉素和磷脂膜的相互作用的模拟中发现,药物分子的方向对含胆固醇的磷脂膜有一定的敏感性,最终会以接近垂直于磷脂膜X-Y面的方式处于膜中。而对于软的不含固醇的磷脂膜,阿霉素在穿膜过程以及膜中稳定结构的方向分布随机性较大。模拟还表明硬的脂质会延迟药物分子的渗透时间,同时我们推测,硬的磷脂膜更加容易滞留药物分子于膜中,这一点与实验结果相吻合。(3)在第三部分论文研究了纳米粒子C60与生物膜的相互作用。与纳米粒子C60在软的纯磷脂膜中的模拟结果类似,C60在硬的加有胆固醇的磷脂膜中也有一个“跳进”的过程,但是时间会有所延迟。由于胆固醇的硬度较大,空间的排开需要一定的模拟时间。同时纳米粒子C60在硬的磷脂膜X-Y面的运动轨迹呈现出笼状效应,即周围的磷脂和胆固醇对C60的运动有强的约束。
[Abstract]:Many cellular functions, such as signal transduction, transmembrane transport and cell membrane fusion, are achieved through the transmembrane of various molecules and substances. The transmembrane mechanism and transmembrane mechanism of biomolecules have been extensively studied in terms of shape and hydrophobicity, of which phospholipid membranes are mostly composed of pure saturated double-stranded phospholipid molecules. There are a lot of transmembrane proteins, sugars, or cholesterol on the phospholipid membrane that change the properties of the membrane, especially the hardness. In order to be closer to the real biofilm system, there are very few studies on the hardness of biomolecules. We have studied the transmembrane mechanism of biological small molecules by using membrane systems with different hardness. In this paper, we use the whole atomic molecular dynamics program to package GROMACSs for the treatment of glycosylphosphatidylinositol (GPI), doxorubicin and nanoparticles of small biomolecules of glycosylphosphatidylinositol. The interaction between C60 and DPPC films with different hardness (including soft pure DPPC films and relatively hard DPPC films containing cholesterol) was systematically studied. The motion state and transmembrane mechanism of biological small molecules with different shapes in phospholipid membrane were studied from the microcosmic point of view. The main contents and conclusions are as follows: 1) glycosylphosphatidylinositol (GPI) is a kind of intermediary connecting anchoring protein to cell membrane. Its molecular structure is mainly composed of carbohydrate molecules and hydrophobic alkyl chain. The biological function is to make the biological signal transfer from one side of the cell membrane to the other side, and realize the signal transmission, because when the glycosylphosphatidylinositol can not enter the membrane normally, This hinders the correct expression of certain biological traits, leading to disease. Studies have shown that glycosylphosphatidylinositol has a hydrophobic tail chain that is very similar to phospholipid. The simulated kinetic process and free energy calculation showed that glycosylphosphatidylinositol could not enter phospholipid membrane spontaneously in pure DPPC membrane. However, it can spontaneously enter the cholesterol-fed phospholipid membrane in a very short simulated time. For GPI, the anchor molecules tend to be located in the hard phospholipid region so that they can successfully anchor the drug molecule doxorubicin. A hydrophobic anticancer drug that has been widely used in clinical practice, but the effect is not high, mainly because of the influence of cell membrane interception. In the simulation of the interaction between doxorubicin and phospholipid membrane, we found that the direction of drug molecules is sensitive to cholesterol containing phospholipid membrane. They end up in the membrane in a manner perpendicular to the X-Y plane of the phospholipid membrane, and for the soft, steroid free phospholipid membrane, The distribution of adriamycin in the membrane and the direction of the stable structure in the membrane is random. The simulation also shows that the hard lipid can delay the permeation time of the drug molecule, and we speculate that the hard phospholipid membrane is more likely to stay the drug molecule in the membrane. This is consistent with the experimental results. (3) in the third part of the paper, the interaction between nanoparticles C60 and biofilm is studied. The simulation results of nano-particle C60 in soft pure phospholipid membrane are similar to that of C60 in hard cholesterol added phospholipids. There is also a "jump" process in the membrane. But the time will be delayed. Because of the high hardness of cholesterol, it takes a certain time for the space to be removed. Meanwhile, the trajectory of the nanoparticles C60 on the X-Y surface of the hard phospholipid membrane shows a caged effect. That is, the surrounding phospholipids and cholesterol on the C 60 movement has strong constraints.
【学位授予单位】：北京化工大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：TQ460.1;TB383.1

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