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

Carnegie Mellon University, Pittsburgh PA

Investigators

Abstract

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.