Functional consequences of plasmalogens - Membrane curvature and lipid miscibility

抽象的。 血浆原的功能后果--膜曲率和脂质 混相性 磷脂酰乙醇胺血浆蛋白原(PEP)广泛存在于哺乳动物的细胞膜上， 在质膜(PM)的内叶中含有20摩尔%的磷脂 根据最近的脂质组学。尽管它很流行，但令人惊讶的是，人们对它知之甚少 它对生物膜的生物物理效应。化学上独特的乙烯基醚 已知甘油主链和sn-1脂肪酰链之间的连接增加 膜的流动性和曲率；然而，PEP将胆固醇分解为更具结构性的胆固醇 质膜的富集区。其独特的曲率属性和角色在 内吞途径和细胞信号表明它破坏了膜的完整性 促进聚变裂变。拟议的研究结合了全原子分子 动力学(MD)与FRET成像和膜融合分析以定量 纯PEP的曲率特性，并表征具有生物学意义的PEP混合物。 该提议是为F32个人培训奖学金。作为研究生、实习生 艾莉森·伦纳德博士(AL)为PEP开发了一个全原子力场，她将在 MD模拟。鉴于AL的研究生研究侧重于开发 单组分膜的脂力场参数和建模，中心 这一提议的假设解决了一个直接适用于人类健康的主题， 脂质动态平衡的机制。艾尔将扩展她的细胞生物学知识和 生物相关脂类混合物的理论模型。

Abstract. Functional consequences of plasmalogens—Membrane curvature and lipid miscibility Phosphatidylethanolamine plasmalogen (PEp) is prevalent in mammalian membranes, comprising 20 mol% of phospholipids in the inner leaflet of the plasma membrane (PM) according to recent lipidomics. Despite its prevalence, surprisingly little is known about its biophysical effects on biological membranes. The chemically unique vinyl ether linkage between the glycerol backbone and sn-1 fatty acyl chain is known to increase membrane fluidity and curvature; yet, PEp partitions into more structured cholesterol rich regions of the plasma membrane. Its unique curvature properties and roles in endocytic pathways and cellular signaling suggest it disrupts membrane integrity to promote fusion and fission. The proposed research combines all-atom molecular dynamics (MD) with FRET imaging and membrane fusion assays to quantify the curvature properties of pure PEp and characterize biologically relevant PEp mixtures. The proposal is for an F32 individual training fellowship. As a graduate student, trainee Dr. Alison Leonard (AL) developed an all-atom force field for PEp which she will use in the MD simulations. Whereas AL's graduate research focused on the development of lipid force field parameters and modeling of single-component membranes, the central hypothesis of this proposal addresses a topic with direct application to human health, the mechanisms of lipid homeostasis. AL will expand her knowledge of cell biology and theoretical modeling of biologically relevant lipid mixtures.