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

卡耐基梅隆大学的马库斯·德瑟诺（Markus Deserno）获得了化学系化学理论、模型和计算方法项目的奖励，研究所谓的“差应力”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组成不同。最近，Deserno认为它们的横向应力也不同（想想拉伸橡胶片的张力）。这影响了许多重要的生物过程，如细胞信号传导、营养摄取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，刚度或组成。由于直接测量差应力仍然是一个重大挑战，因此Deserno将特别强调寻找可以间接确定该值的可观测值，例如，通过相变的变化。PI将与几个实验和计算小组密切协调他的研究，旨在促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，并将被纳入匹兹堡地区高中的几项公共宣传和科学交流活动中。在这个项目中，Deserno博士和他的研究小组旨在建立一个理论框架，量化不同应力如何影响不对称脂质膜的热力学。这样的框架将使我们能够通过实验上可获得的“代理可观察物”来测量细胞膜上的这种差异应力。该理论将在不同粗粒化水平的分子动力学（MD）模拟中进行测试和完善。具体来说，Deserno将研究差应力与四种热力学情况之间的相互作用：(i)液凝胶转变，作为隐藏的机械应力直接耦合到可观察相行为的最清晰的例子；（ii）胆固醇单叶间分布的竞争驱动力，作为揭示其在生理上重要但在很大程度上未知的细胞膜分配的途径；（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、生物物理上与相变更相关的耦合，其含义是源自质膜内部小叶的信号如何被转导到其外部的筏相关信号平台；（iv）半典型脂质交换，这是一个有趣的猜想，关于双层力学如何与脂质重塑酶一起，通过共同调节细胞的脂质组来影响脂质稳态。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.