Collaborative Research: MODULUS: Modeling and Experimental Investigation of Protein Crowding on Lipid Bilayers

合作研究：MODULUS：脂质双层上蛋白质拥挤的建模和实验研究

• 批准号: 1934509
• 负责人: Jeanne Stachowiak
• 金额: $ 42.19万
• 依托单位: University of Texas at Austin
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-10-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1934509&HistoricalAwards=false
• 关键词: Collaborative; Research; MODULUS; Modeling; Experimental

Cellular membranes separate the contents of the cell from the environment. In addition to demarcating cellular boundaries, these membranes perform critical functions such as the uptake of nutrients and drugs into the cell and ejection of material out of the cell. Membranes perform these functions by interacting with many different proteins. Therefore, understanding how membrane-protein interactions take place is critical for gaining insight not just into how cells function but also for understanding how viruses can hijack cells or how better drug delivery systems can be designed. The work proposed here will result in new computational algorithms and experimental tools to understand how cellular membranes interact with proteins to regulate these fundamental functions. The insights generated from our effort will fill major gaps in current understanding about how the cell membrane can change its shape to affect its function. These insights have the potential to benefit society in multiple ways including (i) improving understanding of the mechanisms that pathogens use to invade cells, suggesting new therapeutic strategies; (ii) inspiring the design of better systems for drug and gene delivery, and; (iii) revealing fundamental mechanisms that structure and organize soft matter, potentially leading to improvements in technologies that rely on such materials including surfactants, cosmetics, fuels, and foods. Membrane curvature plays a role in nearly every cellular function, in both health and disease. The curvature of the membrane is mediated by many proteins that interact with lipids. In this proposal, we will develop new theoretical and computational models of membrane-protein interactions with a focus on understanding how protein crowding can lead to membrane curvature generation. This effort combines multiscale modeling of membrane bending with quantitative detailed experimental measurements of membrane surface coverage, steric pressure, and curvature. The multiscale modeling efforts include coarse-grained models of lipid bilayer-protein interactions that will inform the continuum models of membrane curvature generation. The team of investigators includes an experimental biophysicist, a theoretical biophysicist, and mathematicians. The insights generated from our efforts will fill major gaps in current understanding of how membrane curvature is generated and stabilized. We also anticipate these applications driving additional development of the theory and numerical treatment of nonlinear geometric partial differential equations posed on surfaces with constraints. Additionally, the team of investigators will participate in outreach and educational activities, including programs for high school students, undergraduate research opportunities, and new course development. This award was co-funded by Systems and Synthetic Biology in the Division of Molecular and Cellular Biosciences and the Mathematical Biology Program of the Division of Mathematical Sciences.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.

细胞膜将细胞内容物与环境分离。除了划分细胞边界外，这些膜还具有重要的功能，如将营养物质和药物吸收到细胞内以及将物质排出细胞外。膜通过与许多不同的蛋白质相互作用来实现这些功能。因此，了解膜蛋白相互作用是如何发生的，不仅对了解细胞的功能至关重要，而且对了解病毒如何劫持细胞或如何设计更好的药物输送系统也至关重要。这里提出的工作将产生新的计算算法和实验工具，以了解细胞膜如何与蛋白质相互作用以调节这些基本功能。从我们的努力中产生的见解将填补目前对细胞膜如何改变其形状以影响其功能的理解的主要空白。这些见解有可能以多种方式造福社会，包括(i)提高对病原体入侵细胞机制的理解，提出新的治疗策略；（ii）启发设计更好的药物和基因输送系统；（iii）揭示构成和组织软物质的基本机制，可能导致依赖于这些材料的技术的改进，包括表面活性剂、化妆品、燃料和食品。膜曲率在几乎所有的细胞功能中都起着作用，无论是健康还是疾病。膜的弯曲是由许多与脂质相互作用的蛋白质介导的。在本提案中，我们将开发新的膜-蛋白质相互作用的理论和计算模型，重点是了解蛋白质拥挤如何导致膜曲率的产生。这项工作将膜弯曲的多尺度建模与膜表面覆盖、空间压力和曲率的定量详细实验测量相结合。多尺度建模工作包括脂质双层-蛋白质相互作用的粗粒度模型，这将为膜曲率生成的连续模型提供信息。研究小组包括一名实验生物物理学家、一名理论生物物理学家和几名数学家。从我们的努力中产生的见解将填补目前对膜曲率如何产生和稳定的理解的主要空白。我们还预计这些应用将推动非线性几何偏微分方程在约束曲面上的理论和数值处理的进一步发展。此外，研究小组将参与拓展和教育活动，包括高中生项目、本科生研究机会和新课程开发。该奖项由分子和细胞生物科学部的系统和合成生物学以及数学科学部的数学生物学项目共同资助。该奖项反映了美国国家科学基金会的法定使命，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。

项目成果

Membrane bending by protein phase separation

• DOI: 10.1101/2020.05.21.109751
• 发表时间: 2020-05
• 期刊: Proceedings of the National Academy of Sciences
• 作者: Feng Yuan;H. Alimohamadi;Brandon Bakka;Andrea N. Trementozzi;K. Day;N. Fawzi;P. Rangamani;J. Stacho

A Förster Resonance Energy Transfer-Based Sensor of Steric Pressure on Membrane Surfaces.

• DOI: 10.1021/jacs.0c09802
• 发表时间: 2020-12-09
• 期刊: Journal of the American Chemical Society
• 影响因子: 15
• 作者: Houser JR;Hayden CC;Thirumalai D;Stachowiak JC
• 通讯作者: Stachowiak JC