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

运输所需的内体分选复合物催化的膜裂变的多尺度模型

基本信息

批准号：
1661900
负责人：
Saverio Spagnolie
金额：
$ 120万
依托单位：
University of Wisconsin-Madison
依托单位国家：
美国
项目类别：
Continuing Grant
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1661900&HistoricalAwards=false
关键词：
Multi Scale Models Membrane Fission

项目摘要

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.

膜采用广泛的形状，以促进细胞和细胞器水平的特定和中心功能。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理解蛋白质塑造细胞内膜的分子机制。通过数学建模和分析、分子模拟以及与新实验工作的整合，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局限性的工程提供机会。该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），和生物化学和功能实验方法（Audhya）来破译ESCRT复合物催化的膜裂变机制。在连续体水平的数学分析和建模超越了以前的连续体模型，明确包括ESCRT-III长丝的能量和动态特征及其与多组分膜和附近溶剂的相互作用。在原子和粗粒度水平上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力学性质的现实估计。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形成的膜的相互作用，从而导致将在Audhya实验室中测试的特定预测（突变）。实验测试的结果反馈到数学模型和分子模拟的校准和细化。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械理解。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Velocity fluctuations in a dilute suspension of viscous vortex rings

粘性涡环稀悬浮液中的速度波动

DOI：
10.1103/physrevfluids.4.044501
发表时间：
2019
期刊：
Physical Review Fluids
影响因子：
2.7
作者：
Morrell, Thomas A.;Spagnolie, Saverio E.;Thiffeault, Jean-Luc
通讯作者：
Thiffeault, Jean-Luc

Active matter invasion of a viscous fluid: Unstable sheets and a no-flow theorem

DOI：
10.1103/physrevlett.122.098002
发表时间：
2019-03-04
期刊：
PHYSICAL REVIEW LETTERS
影响因子：
8.6
作者：
Miles, Christopher J.;Evans, Arthur A.;Spagnolie, Saverio E.
通讯作者：
Spagnolie, Saverio E.

Helical trajectories of swimming cells with a flexible flagellar hook

DOI：
10.1103/physrevfluids.6.103102
发表时间：
2021-06
期刊：
Physical Review Fluids
影响因子：
2.7
作者：
Zonghao Zou;W. Lough;S. Spagnolie
通讯作者：
Zonghao Zou;W. Lough;S. Spagnolie

Growth factor stimulation promotes multivesicular endosome biogenesis by prolonging recruitment of the late-acting ESCRT machinery.

生长因子刺激通过延长晚效 ESCRT 机制的募集来促进多囊泡内体生物发生。

DOI：
10.1073/pnas.1817898116
发表时间：
2019
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
Quinney,KyleB;Frankel,ElisaB;Shankar,Raakhee;Kasberg,William;Luong,Peter;Audhya,Anjon
通讯作者：
Audhya,Anjon

Dynamic and reversible shape response of red blood cells in synthetic liquid crystals

DOI：
10.1073/pnas.2007753117
发表时间：
2020-10-20
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
影响因子：
11.1
作者：
Nayani, Karthik;Evans, Arthur A.;Abbott, Nicholas L.
通讯作者：
Abbott, Nicholas L.