Abstract

Many research efforts are devoted to improving the efficiency of chemotherapy. One of the aspects is to facilitate the transport of drugs across the cell membranes by attaching the therapeutics to a carrier molecule. The current study focuses on computational investigation of such a system with doxorubicin as the model drug, which is covalently bound to a cell-penetrating peptide. The correct description of its membrane translocation at the molecular level requires proper choice of the model membrane and of the simulation parameters. For the purpose, two phospholipid bilayers are built, one containing solely DPPC and another with mixed lipid content mimicking the composition of a human erythrocyte membrane. Atomistic molecular dynamics simulations are carried out in two types of periodic boundary conditions (2D and 3D PBC), in order to assess the effect of the periodicity dimensionality on the intermolecular interactions. The evolution of some basic characteristics of the bilayers and of the drug–peptide complex is tracked: mass density profiles, electrostatic potentials, lateral diffusion coefficients and areas per lipid, lipid-complex radial distribution functions, secondary structure of the peptide and orientation of the drug relative to the membrane. Thus, the influence of the periodic boundary conditions is quantified and it shows that the mixed system in 3D PBC is the most suitable for analysis of the translocation of the transporting moiety across cell membranes.

摘要

许多研究工作致力于提高化学疗法的效率。方面之一是通过将治疗剂附着到载体分子上来促进药物跨细胞膜的运输。目前的研究集中在以阿霉素为模型药物的这种系统的计算研究上，该系统与细胞穿透肽共价结合。在分子水平上正确描述其膜易位需要正确选择模型膜和模拟参数。为此目的，构建了两个磷脂双层，一个仅包含DPPC，另一个具有模拟人红细胞膜组成的混合脂质含量。在两种类型的周期性边界条件（2D和3D PBC）中进行原子分子动力学模拟，为了评估周期性维数对分子间相互作用的影响。跟踪双层和药物-肽复合物的一些基本特征的演变：质量密度分布图，静电势，侧向扩散系数和每个脂质的面积，脂质复合物的径向分布函数，肽的二级结构和肽的取向药物相对于膜。因此，对周期性边界条件的影响进行了量化，表明3D PBC中的混合系统最适合分析转运部分跨细胞膜的转运。质量密度分布图，静电势，横向扩散系数和每个脂质的面积，脂质复合物的径向分布函数，肽的二级结构以及药物相对于膜的取向。因此，对周期性边界条件的影响进行了量化，表明3D PBC中的混合系统最适合分析转运部分跨细胞膜的转运。质量密度分布图，静电势，横向扩散系数和每个脂质的面积，脂质复合物的径向分布函数，肽的二级结构以及药物相对于膜的取向。因此，对周期性边界条件的影响进行了量化，表明3D PBC中的混合系统最适合分析转运部分跨细胞膜的转运。