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 不同的细胞功能要求脂膜重塑。这种重塑可能是由于某种简单的原因 作为一种蛋白质，它的构象变化与细胞分裂一样复杂。不管目的是什么，改建 能量学由微妙的原子水平的脂-脂、蛋白质-脂和/或蛋白质-蛋白质相互作用决定。 这会导致宏观的膜形状变化和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。这项提议试图量化物理 生物学上重要的膜重塑过程的起源和提出重要的脂-脂/蛋白质-脂 使用分子动力学(MD)和超粗粒度(UCG)模拟的相互作用基序。MD模拟 本质上描述了微妙的蛋白质/脂类相互作用，尽管时间和长度有限。几个问题 目前不能用全原子MD来研究fi，在这种情况下，系统将被极大地简化为fi 访问更大的时间和长度尺度的动力学数据。这种简单的fi连接方法在这里称为UCGing，并且是 一种从全原子模拟中提取动力学数据以告知UCG物理的基于物理的方法 模型(例如，将脂膜表示为fl功能网状结构，并将蛋白质简化为简单的几何结构 形状)。UCGing充当了全原子模拟和实验技术之间的逻辑桥梁，这些技术通常 访问比全原子MD更长的时间和长度尺度。这项建议旨在研究不同情况下的脂质 膜重塑是关键的，但尚未完全了解：i)称为神经节苷脂的特殊脂类之间的相互作用 以及它们与霍乱毒素的强烈相互作用；ii)稳定的脂-脂和蛋白质-脂相互作用 被称为凹陷的大型细胞“酒窝”；以及iii)强烈的蛋白质-蛋白质相互作用，“支架”了一些 人体内最弯曲的脂膜。这项工作支持NIGMS的理解使命 通过描述分子从A°ngstrom到纳米尺度的基本生物结构和过程 以及重要生物事件的精力充沛的细节。除了研究这些具有生物学意义的系统外， 这一奖学金将以培训为中心。培训将包括建立和磨练科学fic、道德和 个人知识将产生一个更成熟和准备好的独立研究人员。