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The Role of Differential Stress in the Physics of Asymmetric Lipid Membranes

差异应力在不对称脂质膜物理学中的作用

基本信息

批准号：
2102316
负责人：
Markus Deserno
金额：
$ 45万
依托单位：
Carnegie-Mellon University
依托单位国家：
美国
项目类别：
Continuing Grant
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-15 至 2024-05-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=2102316&HistoricalAwards=false
关键词：
Role Differential Stress Physics Asymmetric

项目摘要

Markus Deserno of Carnegie Mellon University is supported by an award from the Chemical Theory, Models and Computational Methods program in the Division of Chemistry to investigate how so-called “differential stress” affects the membranes of biological cells. These membranes consist of two leaflets that have long been known to differ in their lipid composition. Recently, Deserno has argued that they also differ in their lateral stress (think of the tension in a stretched sheet of rubber). This impacts many important biological processes, such as cellular signaling, nutrient uptake, and the shaping of intracellular organelles. Deserno will develop theoretical and computational models in the quest to uncover how a stress difference between the leaflets changes many other membrane properties, such as their preferred shape, rigidity, or composition. Since it is still a major challenge to measure differential stress directly, Deserno will place special emphasis on finding observables that allow an indirect determination of this value, for instance, via shifts in phase transitions. The PI will closely coordinate his investigations with several experimental and computational groups, aiming to advance our understanding of a this fundamental cell biological phenomenon. This research will offer training opportunities for graduate and undergraduate students at Carnegie Mellon, and it will be incorporated into several public outreach and science communication activities at high schools in the Pittsburgh area.In this project, Dr. Deserno and his research team aim to develop a theoretical framework that quantifies how differential stress affects the thermodynamics of asymmetric lipid membranes. Such a framework would enable ways of measuring such differential stress on cell membranes via “proxy-observables” that are experimentally accessible. The theory will be tested against and refined by Molecular Dynamics (MD) simulations at different levels of coarse graining. Specifically, Deserno will study the interplay between differential stress and four thermodynamic situations: (i) the liquid-gel transition, as the cleanest example where hidden mechanical stress directly couples to observable phase behavior; (ii) competing driving forces for cholesterol’s inter-leaflet distribution, as a path to uncover its physiologically important but largely unknown partitioning in cellular plasma membranes; (iii) a liquid-ordered/liquid-disordered (lo/ld) phase coexistence, as a more complex but also stronger and biophysically more relevant coupling to a phase transition, with implications for how signals originating in the plasma membrane’s inner leaflet might be transduced to the raft-associated signaling platforms on its outer side; and (iv) semi-grand canonical lipid exchange, as an intriguing conjecture for how bilayer mechanics, in conjunction with lipid remodeling enzymes, could affect lipid homeostasis by co-regulating a cell’s lipidome.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.

卡内基梅隆大学的 Markus Deserno 获得了化学系化学理论、模型和计算方法项目的奖项，以研究所谓的“差异应力”如何影响生物细胞膜。这些膜由两个小叶组成，人们早就知道它们的脂质成分不同。最近，Deserno 认为它们的侧向应力也不同（想想拉伸橡胶片的张力）。这会影响许多重要的生物过程，例如细胞信号传导、营养吸收和细胞内细胞器的形成。 Deserno 将开发理论和计算模型，以揭示小叶之间的应力差异如何改变许多其他膜特性，例如它们的首选形状、刚性或成分。由于直接测量差异应力仍然是一个重大挑战，Deserno 将特别强调寻找可间接确定该值的可观测值，例如通过相变的变化。首席研究员将与几个实验和计算小组密切协调他的研究，旨在增进我们对这一基本细胞生物学现象的理解。这项研究将为卡内基梅隆大学的研究生和本科生提供培训机会，并将纳入匹兹堡地区高中的多项公共宣传和科学传播活动。在这个项目中，Deserno 博士和他的研究团队旨在开发一个理论框架，量化差异应力如何影响不对称脂质膜的热力学。这样的框架将能够通过实验上可访问的“代理可观察量”来测量细胞膜上的这种差异应力。该理论将通过不同粗粒度水平的分子动力学 (MD) 模拟进行测试和完善。具体来说，Deserno 将研究差异应力与四种热力学情况之间的相互作用：(i) 液体-凝胶转变，这是隐藏的机械应力直接与可观察的相行为耦合的最简单的例子； (ii) 胆固醇小叶间分布的竞争驱动力，作为揭示其在细胞质膜中生理上重要但很大程度上未知的分配的途径；（iii）液体有序/液体无序（lo/ld）相共存，作为一种更复杂但也更强且在生物物理上更相关的相变耦合，对源自质膜内叶的信号如何转导到其外侧与筏相关的信号平台有影响； (iv) 半大规范脂质交换，作为双层力学如何与脂质重塑酶结合，通过共同调节细胞脂质组来影响脂质稳态的有趣猜想。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力价值和更广泛的影响审查进行评估，被认为值得支持标准。