The molecular study of lipid membrane curvature generation and sustainment mechanisms using all-atom and ultra-coarse-grained simulations.

使用全原子和超粗粒度模拟对脂质膜曲率生成和维持机制进行分子研究。

• 批准号: 10026319
• 负责人: Andrew Harrison Beaven
• 金额: --
• 依托单位: U.S. NATIONAL INST/CHILD HLTH/HUMAN DEV
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10026319
• 关键词: Binding; Biological; Caveolae; Caveolins; Cell division; Cell physiology; Cells; Childhood; Cholera Toxin; Complex; Computer software; Coupling; Cytoprotection; Data; Degradation Pathway; Diffuse; Diffusion; Disease; Dynamin; Electrostatics; Environment; Equilibrium; Ethics; Event; Exhibits; Fellowship; Filament; Free Energy; Future; Ganglioside GM1; Gangliosides; Gangliosidoses; Generations; Goals; Grain; Health; Homeostasis; Human; Human body; Hydrogen Bonding; Integral Membrane Protein; Knowledge; Lateral; Lead; Length; Life; Lipids; Mechanics; Membrane; Membrane Lipids; Metabolic; Methods; Minor; Mission; Modeling; Molecular; Molecular Conformation; National Institute of General Medical Sciences; Neck; Pathway interactions; Physics; Polymers; Process; Protein Conformation; Proteins; Receptor Cell; Research Personnel; Scaffolding Protein; Shapes; Signal Transduction; Specificity; Structure; Surface; System; Techniques; Testing; Time; Toxin; Training; Virus; Work; base; flasks; molecular dynamics; molecular scale; nanoscale; novel; preference; protein oligomer; protein protein interaction; receptor; receptor mediated endocytosis; repository; scaffold; simulation

Abstract / Project Summary Diverse cellular functions require lipid membrane remodeling. This remodeling can be due to something as simple as a protein changing conformation to as complex as cell division. Regardless of the purpose, the remodeling energetics are determined by delicate, atomic-level lipid-lipid, protein-lipid, and / or protein-protein interactions that lead to macroscopic membrane shape changes and underline diseases involving local lipid concentration, cellular toxin / virus entry, and how the cell maintains its integrity. This proposal seeks to quantify the physical origins of biologically important membrane remodeling processes and propose important lipid-lipid / protein-lipid interaction motifs using molecular dynamics (MD) and ultra-coarse-grained (UCG) simulations. MD simulations inherently describe delicate protein / lipid interactions albeit on limited time- and length-scales. Some problems cannot be efficiently studied using all-atom MD, and in these cases, the systems will be drastically simplified to access larger time- and length-scale dynamics data. This simplification method is called UCGing herein, and is a physics-based method of extracting dynamics data from all-atom simulations to inform the physics of the UCG model (e.g., a lipid membrane is represented as a fluctuating mesh and proteins are reduced to simple geometric shapes). UCGing acts as a logical bridge between all-atom simulations and experimental techniques that typically access longer time- and length-scales than all-atom MD. This proposal aims to study diverse situations where lipid membrane remodeling is critical and not fully understood: i) interactions between special lipids called gangliosides as well as their strong interactions with cholera toxin; ii) the lipid-lipid and protein-lipid interactions that stabilize large cellular “dimples” called caveolae; and iii) the strong protein-protein interactions that “scaffold” some of the most highly curved lipid membranes in the human body. This work supports the NIGMS mission of understanding fundamental biological structures and processes at the A° ngstrom- to nanometer-scale by describing molecular and energetic detail of important biological events. In addition to studying these biologically meaningful systems, this fellowship will be centered around training. Training will include building and honing scientific, ethical, and personal knowledge that will produce a more mature and readied independent researcher.

摘要/项目摘要 不同的细胞功能需要脂质膜重塑。这种重塑可能是由于一些简单的东西， 像蛋白质一样改变构象，变得像细胞分裂一样复杂。不管是什么目的， 能量学是由精细的、原子水平的脂质-脂质、蛋白质-脂质和/或蛋白质-蛋白质相互作用决定的 导致宏观膜形状变化和涉及局部脂质浓度的潜在疾病， 细胞毒素/病毒进入，以及细胞如何保持其完整性。该建议旨在量化物理 生物学上重要的膜重塑过程的起源，并提出重要的脂质-脂质/蛋白质-脂质 使用分子动力学（MD）和超粗粒（UCG）模拟的相互作用图案。MD模拟 固有地描述了精细蛋白质/脂质相互作用，尽管在有限的时间和长度尺度上。一些问题 不能有效地研究使用全原子MD，在这些情况下，系统将大大简化艾德， 访问更大的时间和长度尺度的动态数据。这种简化方法在本文中被称为UCGing， 一种基于物理学的方法，从全原子模拟中提取动力学数据，为UCG的物理学提供信息 模型（例如，脂质膜被表示为一个起伏的网格，蛋白质被简化为简单的几何形状。 形状）。UCGing作为全原子模拟和实验技术之间的逻辑桥梁， 获得比全原子MD更长的时间和长度尺度。该提案旨在研究脂质 膜重塑是至关重要的，但尚未完全了解：i）称为神经节苷脂的特殊脂质之间的相互作用 以及它们与霍乱毒素的强烈相互作用; ii）稳定 大的细胞“酒窝”称为小窝;和iii）强蛋白质-蛋白质相互作用，“支架”的一些 人体内最弯曲的脂膜。这项工作支持了NIGMS的理解使命 基本的生物结构和过程在A° ngstrom-到纳米尺度通过描述分子 重要生物事件的细节。除了研究这些有生物学意义的系统， 这个奖学金将以培训为中心。培训将包括建立和磨练科学，道德， 个人知识，将产生一个更成熟和准备独立的研究人员。