Membranes adopt a broad range of shapes to facilitate specific and central functions at the level of cells and organelles. Proteins and lipids play a key role in this process, but their molecular choreography is still emerging and their impact on altering membrane shape in vivo remains controversial and obscure. A central challenge in cell biology is to understand the molecular mechanisms by which intracellular membranes are shaped by proteins. Deciphering these mechanisms, through mathematical modeling and analysis, molecular simulations, and integration with new experimental efforts, will revolutionize our view of biology and provide opportunities for engineering that extend the limitations of natural biological systems.
This project tightly integrates mathematical theory (Spagnolie), molecular simulations at atomistic and coarse-grained levels (Cui), and biochemical and functional experimental approaches (Audhya) to decipher the mechanism of membrane fission catalyzed by the ESCRT complexes. The mathematical analysis and modeling at the continuum level goes beyond previous continuum models to explicitly include the energetic and dynamic features of ESCRT-III filaments and their interactions with the multi-component membrane and nearby solvent. Molecular simulations at atomic and coarse-grained levels provide realistic estimates of mechanical and dynamic properties of proteins and membrane required in the mathematical analysis. Numerical simulations and asymptotic analysis will identify the physical properties of ESCRT-III subunits and their interactions with the membrane that drive membrane vesiculation, leading to specific predictions (mutations) that will be tested in the Audhya lab. Results of experimental tests feed back to the calibration and refinement of the mathematical models and molecular simulations. The iterative process that integrates multi-scale computations and experimental investigation will establish a powerful paradigm to advance our mechanistic understanding of complex biological processes.