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

细胞膜将细胞内的物质与环境隔开。除了划定细胞边界外，这些膜还发挥着关键功能，如将营养物质和药物吸收到细胞内，以及将物质排出细胞。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-蛋白质相互作用是如何发生的，不仅对于洞察细胞的功能至关重要，而且对于了解病毒如何劫持细胞或如何设计更好的药物输送系统至关重要。这里提出的工作将导致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。我们的努力所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；以及(Iii)揭示软物质的结构和组织的基本机制，可能导致依赖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。无论是在健康还是疾病中，细胞膜的弯曲几乎在每一种细胞功能中都起着作用。膜的曲率是由许多与脂类相互作用的蛋白质调节的。在这项提案中，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率、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，这将为膜曲率产生的连续模型提供信息。研究团队包括一名实验生物物理学家、一名理论生物物理学家和数学家。我们的努力所产生的见解将填补目前对膜曲率是如何产生和稳定的理解的主要空白。我们也期待着这些应用推动在有约束的曲面上提出的非线性几何偏微分方程的理论和数值处理的进一步发展。此外，调查团队将参与外展和教育活动，包括针对高中生的计划、本科生研究机会和新课程开发。该奖项是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的。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.