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: 1934411
• 负责人: Padmini Rangamani
• 金额: $ 58.87万
• 依托单位: University of California-San Diego
• 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 2024-09-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1934411&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.

细胞膜将细胞的内容物与环境隔开。除了划分细胞边界外，这些膜还执行关键功能，例如将营养物质和药物吸收到细胞中以及将物质排出细胞。膜通过与许多不同的蛋白质相互作用来执行这些功能。因此，了解膜-蛋白质相互作用如何发生不仅对于了解细胞如何发挥功能至关重要，而且对于了解病毒如何劫持细胞或如何设计更好的药物递送系统也至关重要。本文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来调节这些基本功能。从我们的努力中产生的见解将填补目前关于细胞膜如何改变其形状以影响其功能的理解中的主要空白。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的机制的理解，提出新的治疗策略;（ii）启发设计更好的药物和基因递送系统;以及（iii）揭示软物质结构和组织的基本机制，潜在地导致依赖于包括表面活性剂、化妆品、燃料和食品的这些材料的技术的改进。膜曲率在健康和疾病中几乎每一种细胞功能中都起着作用。膜的弯曲由许多与脂质相互作用的蛋白质介导。在这项提案中，我们将开发新的膜蛋白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。这项工作结合了多尺度建模的膜弯曲定量详细的实验测量膜表面覆盖，空间压力和曲率。多尺度建模工作包括粗粒度模型的脂质双层蛋白质相互作用，将通知膜曲率生成的连续模型。研究小组包括一名实验生物药理学家、一名理论生物药理学家和数学家。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中的主要空白。我们还预计这些应用程序驱动的理论和数值处理的非线性几何偏微分方程的表面上的约束的额外发展。 此外，研究人员团队将参加外展和教育活动，包括高中生计划，本科生研究机会和新课程开发。该奖项由分子与细胞生物科学部的系统与合成生物学和数学科学部的数学生物学项目共同资助。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。

项目成果

The ins and outs of membrane bending by intrinsically disordered proteins.

• DOI: 10.1126/sciadv.adg3485
• 发表时间: 2023-07-07
• 期刊: SCIENCE ADVANCES
• 影响因子: 13.6
• 作者: Yuan, Feng;Lee, Christopher T.;Sangani, Arjun;Houser, Justin R.;Wang, Liping;Lafer, Eileen M.;Rangamani, Padmini;Stachowiak, Jeanne C.
• 通讯作者: Stachowiak, Jeanne C.

Membrane bending by protein phase separation.

通过蛋白质相分离使膜弯曲。

• DOI: 10.1073/pnas.2017435118
• 发表时间: 2021
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Yuan,Feng;Alimohamadi,Haleh;Bakka,Brandon;Trementozzi,AndreaN;Day,KaseyJ;Fawzi,NicolasL;Rangamani,Padmini;Stachowiak,JeanneC
• 通讯作者: Stachowiak,JeanneC