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 多种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原因造成的。 作为蛋白质改变构象，就像细胞分裂一样复杂，无论其目的如何，重塑。 能量由微妙的原子级脂质-脂质、蛋白质-脂质和/或蛋白质-蛋白质相互作用决定 导致宏观膜形状变化并强调涉及局部脂质浓度的疾病， 细胞毒素/病毒进入，以及细胞如何保持其完整性该提案旨在量化物理。 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）和超粗粒度（UCG）模拟的相互作用基序。 尽管在有限的时间和长度范围内存在一些问题，但本质上描述了微妙的蛋白质/脂质相互作用。 无法使用全原子 MD 进行有效研究，在这些情况下，系统将大大简化为 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，并且被称为 UCGing。 一种基于物理的方法，从全原子模拟中提取动力学数据，以了解 UCG 的物理原理 模型（例如，脂质膜被表示为波动的网格，蛋白质被简化为简单的几何形状 UCGing 充当全原子模拟和通常的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的不同情况。 膜重塑至关重要，但尚未完全理解：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) 稳定的脂质-脂质和蛋白质-脂质相互作用； 称为小凹的大细胞“凹坑”；以及 iii) 强大的蛋白质-蛋白质相互作用，“支撑”一些细胞。 这项工作支持 NIGMS 的理解使命。 通过描述分子，了解 A° 埃到纳米尺度的基本生物结构和过程 除了研究这些具有生物学意义的系统之外， 该奖学金将以培训为中心，包括建立和磨练科学、道德和道德。 个人知识将培养出更成熟、更有准备的独立研究人员。