Abstract：
Monosialoganglioside (GM1), a ubiquitous component of lipid rafts, and hemin, an integral part of heme proteins such as hemoglobin, are essential to the cell membranes of brain neurons and erythrocyte red blood cells for regulating cellular communication and oxygen transport. Protoporphyrin IX (PPIX) and its derivative hemin, on the contrary, show significant cytotoxic effects when in excess causing hematological diseases, such as thalassemia, anemia, malaria, and neurodegeneration. However, the in-depth molecular etiology of their interactions with the cell membrane has so far been poorly understood. Herein, the structure of the polymer cushion-supported lipid bilayer (SLB) of the binary mixture of phospholipid and GM1 in the presence of PPIX and its derivative hemin has been investigated to predict the molecular interactions in model phospholipid membranes. A high-resolution synchrotron-based X-ray scattering technique has been employed to explore the out-of-plane structure of the assembly at different compositions and concentrations. The structural changes have been complemented with the isobaric changes in the mean molecular area obtained from the Langmuir monolayer isotherm to predict the additive-induced membrane condensation and fluidization. PPIX-induced fluidization of phospholipid SLB without GM1 was witnessed, which was reversed to condensation with 2-fold higher structural changes in the presence of GM1. A hemin concentration-dependent linear condensing effect was observed in the pristine SLB. The effect was significantly reduced, and the linearity was observed to be lost in the mixed SLB containing GM1. Our study shows that GM1 alters the interaction of hemin and PPIX with the membrane, which could be explained with the aid of hydrophobic and electrostatic interactions. Our study indicates favorable and unfavorable interactions of GM1 with PPIX and hemin, respectively, in the membrane. The observed structural changes in both SLB and the underlying polymer cushion layer lead to the proposal of a molecule-specific interaction model that can benefit the pharmaceutical industries specialized for drug designing. Our study potentially enriches our fundamental biophysical understanding of neurodegenerative diseases and drug-membrane interactions.
摘要：
单唾液酸神经节苷脂（GM1），一种普遍存在的脂筏成分，和血红素,血红素蛋白如血红蛋白的组成部分，对于调节细胞通讯和氧气运输的大脑神经元和红细胞红细胞的细胞膜至关重要。原卟啉IX（PPIX）及其衍生物血红素，相反,当过量引起血液系统疾病时显示出显著的细胞毒性作用，比如地中海贫血，贫血,疟疾,和神经变性。然而,到目前为止，人们对它们与细胞膜相互作用的深入分子病因知之甚少。在这里，已经研究了在PPIX及其衍生物血红素存在下磷脂和GM1二元混合物的聚合物垫支持的脂质双层（SLB）的结构，以预测模型磷脂膜中的分子相互作用。已采用基于高分辨率同步加速器的X射线散射技术来探索不同成分和浓度的组件的平面外结构。结构变化已与从Langmuir单层等温线获得的平均分子面积的等压变化相结合，以预测添加剂引起的膜冷凝和流化。PPIX诱导的无GM1磷脂SLB流态化，在存在GM1的情况下，结构变化提高了2倍，从而逆转为缩合。在原始SLB中观察到血红素浓度依赖性线性缩合效应。效果明显下降，并且观察到在含有GM1的混合SLB中失去了线性。我们的研究表明，GM1改变了血红素和PPIX与膜的相互作用，这可以用疏水和静电相互作用来解释。我们的研究表明GM1与PPIX和血红素的有利和不利的相互作用，分别,在膜中。在SLB和底层聚合物垫层中观察到的结构变化导致了分子特异性相互作用模型的提出，该模型可以使专门用于药物设计的制药行业受益。我们的研究可能丰富了我们对神经退行性疾病和药物-膜相互作用的基本生物物理理解。
