Multiscale Modeling of Phase Transitions Driven by Multivalency and Disordered Proteins

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This project will uncover how biological matter is organized into tiny functional compartments inside cells. These compartments resemble liquid droplets. They are known as membraneless organelles and they perform different functions in different types of cells. They collect different types of molecules and form in different locations within cells. An example of a specific membraneless organelle is one that collects key protein and RNA molecules to assist in the formation of connections in the brain. This is essential for learning and the development of memories. Distinct protein molecules drive the formation of distinct membraneless organelles. In some cases, the identities of the relevant proteins are known. It is also known that membraneless organelles form by processes known as phase separation, which are similar to processes that lead to the separation of oil from vinegar. Research in this project will uncover the relationships between specific proteins and the physical and chemical interactions that lead to the formation of membraneless organelles via phase separation. This research is important because membraneless organelles control a variety of cellular functions that can go wrong and give rise to diseases. The research will use computations that combine physics and chemistry to answer biologically relevant questions. The research will also fuel the development of specific instruction modules, which will be used in the INSPIRE program at Washington University. The goal is to attract rising high-school freshmen from the St. Louis area and teach them the importance of quantitative sciences for driving discoveries in biology. This will help prepare the next generation of scientists to take on technological challenges at the intersection of physics, chemistry, mathematics and biology.Membrane-less organelles are dense, highly viscous liquids that form via liquid-liquid phase separation. This refers to the separation of polymers into dense, polymer-rich liquids that are in equilibrium with polymer-poor dispersed phases. It is often the case that a single protein is necessary and sufficient to drive the formation of a specific organelle. Multivalent interactions and intrinsic disorder are defining features of proteins that drive phase separation. The project will focus on the specificity of interactions among short linear motifs, their valencies, and the patterning of motifs in archetypal sequences that drive phase separation. The research will also test specific predictions that have been made recently regarding the role of disordered linkers as modulators of the phase behavior of multidomain proteins. A suite of novel multiscale, multiresolution, high-throughput computational methods will drive the project research. These will be combined with experiments in test tubes and in cells. The experiments will be performed in collaboration with accomplished investigators in the field of intracellular phase separation. Polymer physics theories will be adapted to facilitate integration of computational results with experimental data. Integration of the results investigations using polymer physics theories will lead to a comprehensive understanding of how sequence features of low complexity IDPs influence the driving forces for phase separation.This project is jointly funded by the Molecular Biophysics Cluster in the Division of Molecular and Cellular Biosciences and the Physics of Living Systems Program in the Division of Physics.