Madhusmita Tripathy (TU Darmstadt)

Probing the Microscopic Origin of Plasma Membrane Heterogeneity and its Function in Molecular Simulations

Host: Andreas Heuer

Plasma membrane heterogeneity has long been implicated in various cellular functions such as cell signaling and vesicle trafficking. However, their molecular origin and mechanistic principles governing their function are so far not well understood, as their nanoscopic and highly dynamic nature limit both direct experimental measurements and their interpretation [1]. In this context, computer simulation holds immense potential to investigate both the molecular-level interactions that lead to PM heterogeneity and the mechanisms that govern their functions. Herein, we employ molecular simulation to study various ternary model membranes, with distinct lipid chemistry, that exhibit coexisting liquid ordered (Lo) and liquid disordered (Ld) phases. Taking inspiration from the physics of amorphous systems, we characterize membrane lateral heterogeneity using a non-affine deformation framework [2] and probe the transverse heterogeneity in terms of the three-dimensional lipid packing defects [3], both of which can be considered as conjugates. Using these two, we formalize the intuitive, yet largely unexplored, connection between local membrane order and lipid packing. We use this connection to explore the mechanistic principles behind preferential localization of proteins in mixed phase membranes and membrane permeability of small molecules. Our observations suggest that heterogeneity in liquid membranes follow some generic features, where functions may arise based on packing-related basic design principles [4]. ( [1] Erdinc Sezgin, Ilya Levental, Satyajit Mayor, and Christian Eggeling (2017) Nature Reviews Molecular Cell Biology [2] Sahithya S. Iyer, Madhusmita Tripathy, and Anand Srivastava (2018) Biophysical Journal [3] Madhusmita Tripathy, Subasini Thangamani, Anand Srivastava (2020) Journal of Chemical Theory and Computation [4] Madhusmita Tripathy, Anand Srivastava (2023) Biophysical Journal )

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