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 各种细胞功能需要脂质膜重塑。这种重塑可能是由于简单的东西 作为一种蛋白质的变化构象与细胞分裂一样复杂。无论目的是什么，重塑 能量由精致的原子级脂质脂质，蛋白质脂质和 /或蛋白质 - 蛋白质相互作用确定 这导致宏观膜形状变化和涉及局部脂质浓度的疾病， 细胞毒素 /病毒的进入，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和建议 使用分子动力学（MD）和超晶粒（UCG）模拟的相互作用基序。 MD模拟 固有地描述了精致的蛋白质 /脂质相互作用，尽管时间和长度尺度有限。一些问题 无法使用全原子MD进行有效研究，在这些情况下，系统将大幅简化为 访问更大的时间和长度尺度动力学数据。这种简化的方法在本文中称为Ucing，是 一种基于物理学的方法，用于从全原子模拟中提取动态数据，以告知UCG的物理 模型（例如，脂质膜表示为闪烁的网格，蛋白质还原为简单的几何形状 形状）。 Ucging充当全原子模拟和实验技术之间的逻辑桥 访问比全原子MD更长的时间和长度尺度。该建议旨在研究脂质的潜水情况 膜重塑至关重要，尚不完全理解：i）特殊脂质之间的相互作用称为神经节剂 以及他们与霍乱毒素的强烈互动； ii）稳定的脂质脂质和蛋白质脂质相互作用 大细胞“酒窝”称为小窝； iii）强烈的蛋白质 - 蛋白质相互作用，这些相互作用“脚手架”一些 人体中最高度弯曲的脂质膜。这项工作支持诺格姆斯的理解使命 ngstrom-至纳米尺度的基本生物学结构和过程通过描述分子 重要的生物事件的充满活力的细节。除了研究这些生物学有意义的系统外， 该奖学金将集中在培训围绕培训围绕。培训将包括建造和磨练科学，道德和 个人知识将产生一个更加成熟且良好的独立研究人员。