Collaborative Research: Mapping protein-membrane interactions from molecules to cell-level dynamics

合作研究：绘制从分子到细胞水平动力学的蛋白质-膜相互作用

• 批准号: 2217662
• 负责人: Michael Grabe
• 金额: $ 53.88万
• 依托单位: University of California-San Francisco
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2217662&HistoricalAwards=false
• 关键词: Collaborative; Research; Mapping; protein; membrane

Biological membranes that surround the cell, and organelles within the cell, are complex mixtures of proteins and phospholipids, distinct classes of biological molecules which combine to seal off the cell and its compartments. How proteins and phospholipids work together to enable the processes that must work across these barriers is not well understood. The project will investigate the interwoven dynamics coupling cellular membrane shape with embedded protein orientations and aggregation. The research will explore the role of membrane-mediated protein aggregations in the clustering of viral coat proteins that facilitates the entry and exit of viral particles (e.g., Covid and influenza) from cells, the activation of membrane channels in processes like touch sensation, and the involvement of membrane proteins in the creation of mitochondrial membrane shape, which aids in maximizing cellular energy production. Answers to these questions can lead to novel therapeutics for viruses and to a deeper understanding of cell physiology. The project will specifically lead to a mapping from the structure and composition of individual proteins to the large-scale motions of the membranes in which they are embedded, providing a general physics-based understanding of cellular membrane processes. The research will form a foundation for interdisciplinary graduate student training and as a foundation for outreach to STEM undergraduates and K12 students in the Tucson and San Francisco areas. Constructing models that properly describe how atomic level interactions lead to mesoscale membrane distortions poses a grand challenge. The research proposed here meets this challenge using a multiscale approach to develop chemically accurate descriptions of the interaction between integral membrane proteins and the surrounding membrane that is then feed upwards to create a realistic continuum model of protein-driven membrane morphology at the cell level. The project will use molecular dynamics simulations to determine the interaction of a single protein with a membrane and how small groups of proteins interact and deform membranes. These simulations will be carried out on a set of proteins with distinct geometric and chemical properties. The results from these simulations will then be used to parameterize a continuum level model of protein-membrane interactions that will be used to explore the cell-level membrane dynamics involved in viral pathogenesis, mitochondrial morphogenesis, and PIEZO channels in mechanosensation. The algorithms that are developed will be applicable to a range of problems in the dynamics of surfaces, thereby impacting research in biology, biomedical science, physics, and engineering and will be made freely-available to the community. The training that is proposed will support students and postdocs in a broadly interdisciplinary research plan that crosses multiple length scales and spans molecular biology and cellular biophysics.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

包围细胞的生物膜和细胞内的细胞器是蛋白质和磷脂的复杂混合物，蛋白质和磷脂是不同类别的生物分子，它们联合收割机组合以封闭细胞及其隔室。蛋白质和磷脂如何共同作用，使必须跨越这些障碍的过程还没有得到很好的理解。该项目将研究细胞膜形状与嵌入蛋白质方向和聚集之间的交织动力学。这项研究将探索膜介导的蛋白质聚集在病毒外壳蛋白聚集中的作用，这些蛋白质聚集促进病毒颗粒的进入和离开（例如，新冠病毒和流感）从细胞中，膜通道在触觉等过程中的激活，以及膜蛋白参与线粒体膜形状的形成，这有助于最大限度地提高细胞能量的产生。这些问题的答案可以导致病毒的新疗法和对细胞生理学的更深入理解。该项目将具体导致从单个蛋白质的结构和组成到它们嵌入的膜的大规模运动的映射，提供对细胞膜过程的一般物理学理解。该研究将形成跨学科研究生培训的基础，并作为图森和弗朗西斯科地区STEM本科生和K12学生的基础。构建适当描述原子水平相互作用如何导致中尺度膜扭曲的模型是一个巨大的挑战。这里提出的研究使用多尺度方法来应对这一挑战，以开发完整膜蛋白与周围膜之间相互作用的化学准确描述，然后向上馈送，以在细胞水平上创建蛋白质驱动的膜形态的现实连续模型。该项目将使用分子动力学模拟来确定单个蛋白质与膜的相互作用以及小群体蛋白质如何相互作用并使膜变形。这些模拟将在一组具有不同几何和化学性质的蛋白质上进行。然后，这些模拟的结果将用于参数化蛋白质-膜相互作用的连续水平模型，该模型将用于探索参与病毒发病机制、线粒体形态发生和机械感觉中的PIEZO通道的细胞水平膜动力学。开发的算法将适用于表面动力学中的一系列问题，从而影响生物学，生物医学科学，物理学和工程学的研究，并将免费提供给社区。该培训计划将支持学生和博士后进行跨学科的研究计划，该计划跨越多个长度尺度，涵盖分子生物学和细胞生物物理学。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。