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

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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.