A theoretical and computational study of the interaction between biomembranes and curved proteins

• Autores: Caterina Tozzi
• Directores de la Tesis: Marino Arroyo Balaguer (dir. tes.)
• Lectura: En la Universitat Politècnica de Catalunya (UPC) ( España ) en 2021
• Idioma: español
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• Resumen

  • Organelles are the smallest functional parts of eukaryotic cells. Among them, some are membrane-bound such as the nucleus, the endoplasmic reticulum, or the Golgi apparatus, each of them with essential biological functions. In order to accomplish cell functions, membranes enclosing these organelles continuously adapt their shapes through the out-of-equilibrium interaction with macro-molecules, notably proteins.

    During the life of cells, proteins are main actors in membrane bending dynamics since they have the ability to impinge their curvature onto the membrane, and generate transiently highly curved structures, such as tubes and spherical buds. How proteins can remodel the different organelles has been broadly studied in equilibrium, but a clear understanding of the complex chemo-mechanical problem that drives membrane reshaping out-of-equilibrium is still lacking.

    In the first Part of the thesis we develop a general theoretical and computational framework for the dynamics of curved proteins adhered to lipid membranes. The theory is based on a nonlinear Onsager's principle, a variational method for irreversible thermodynamics. The resulting governing equations and numerical simulations provide a foundation to understand the dynamics of curvature sensing, curvature generation, and more generally membrane curvature mechano-chemistry, as illustrated by a selection of test cases. We show that continuum modeling is a powerful instrument to describe the protein-membrane interaction. However, this model does not account for the orientational order of proteins and its derivation lacks a microscopic basis.

    To address these limitations, in the second Part of the thesis we develop a mean-field density functional theory to predict the orientational order and evaluate the free-energy of ensembles of elongated and curved objects, such as BAR proteins, on curved membranes. This kind of protein may adopt different states of orientational order, from isotropic to nematic. The theory is tightly coupled to the microscopic properties of the proteins and explains how a density-dependent isotropic-to-nematic transition is modified by the anisotropic underlying curvature of the membrane. This work lays the ground to understand the interplay between the molecular organization of proteins and the membrane shape dynamics. We explore the coexistence of isotropic and nematic phases on differently curved lipid membranes. We explain, both experimentally and through modelling, how a BAR protein binds on differently curved membrane templates and reshapes them based while modifying their microscopic organization. Our results broaden our understanding of the reshaping dynamics by BAR proteins on mechanically constrained membranes, and provide a framework to understand biological responses involving BAR proteins to membrane-mediated mechanical stimuli.