Multi-Scale Models for Membrane Fission Catalyzed by the Endosomal Sorting Complexes Required for Transport

膜采用广泛的形状，以促进细胞和细胞器水平上的特定和中心功能。蛋白质和脂质在这一过程中起着关键作用，但它们的分子编排仍在出现，它们对改变体内膜形状的影响仍然存在争议和模糊。细胞生物学的一个核心挑战是了解细胞膜由蛋白质形成的分子机制。通过数学建模和分析、分子模拟以及与新的实验努力相结合来破译这些机制，将彻底改变我们对生物学的看法，并为扩展自然生物系统的局限性的工程提供机会。本项目紧密结合数学理论（Spagnolie）、原子和粗粒度水平的分子模拟（Cui）以及生化和功能实验方法（Audhya）来解读ESCRT复合物催化膜裂变的机制。在连续统水平上的数学分析和建模超越了以往的连续统模型，明确地包括ESCRT-III细丝的能量和动力学特征以及它们与多组分膜和附近溶剂的相互作用。原子和粗粒度水平的分子模拟提供了数学分析所需的蛋白质和膜的机械和动态特性的现实估计。数值模拟和渐近分析将确定ESCRT-III亚基的物理特性及其与驱动膜囊泡的膜的相互作用，从而导致将在Audhya实验室进行测试的特定预测（突变）。实验测试的结果反馈给数学模型和分子模拟的校准和改进。集成多尺度计算和实验研究的迭代过程将建立一个强大的范式，以推进我们对复杂生物过程的机制理解。

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.