Computer design and functional prediction of dendritic polypeptides树枝形多肽的计算机设计及功能预测.pdfVIP

    中文摘要 本论文采用粗粒化分子动力学模拟方法来研究在低和中性pH 条件下，第三代表 面修饰短肽的树枝状分子（G3-HHHR ）与脂质膜相互作用。短肽包含三个对pH 敏感 的组氨酸和一个末端的精氨酸。通过模拟，我们发现在中性pH 条件下，这类末端修 饰短肽的树枝状大分子发生了一定的形变并且吸附于非对称膜的表面，在低pH 条件 下，由于强烈的静电吸引作用，这类大分子嵌入了带负电的膜中，自身的形状呈哑铃 状。这类大分子使下半部分带负电的脂质分子翻转至膜的上半部分，且引起膜变薄进 而促进膜渗透现象的发生。我们的研究为这类的大分子应用于载药和基因输运方面提 供了有益的帮助。基于该类分子吸附于膜和致使膜发生渗透现象对pH 环境的依赖性， 本文提出了一种可能的利用运载基因来治疗癌症的途径。 关键词：树枝状分子；脂质膜；表面修饰；相互作用；粗粒化分子动力学模拟； 基因输运 作 者：屠晨坤 指导教师：马余强、田文得 I   Abstract In this article, the interactions between a G3 PAMAM dendrimer modified by 32 tetrapeptides of the HHHR amine acid sequence and lipid bilayers in two pH environments were investigated by coarse-grained molecular dynamics simulations within the MARTINI force field. The simulation results reveal that the dendrimer-peptide conjugate deforms and becomes flat on the asymmetrical, electronegative membrane at physiological pH. And, it inserts into the lipid bilayer forming a dumbbell-like structure at low pH driven by the enhanced electrostatic attraction from the bottom leaflet of the membrane. The introduction of peptide-dendrimer conjugate can promote the flop of negatively charged lipids from the bottom leaflet to the top leaflet and cause the local membrane thinning which improves the membrane permeability. Our results provide useful information for the potential applications of peptide-dendrimer conjugates in the drug and gene delivery. Based on the results, a possible route for gene delivery using the nonspecific electrostatic interaction regulated by pH environments was suggested. Keyw