@article{20318, abstract = {Lipid membranes and membrane deformations are a long-standing area of research in soft matter and biophysics. Computer simulations have complemented analytical and experimental approaches as one of the pillars in the field. However, setting up and using membrane simulations can come with barriers due to the multidisciplinary effort involved and the vast choice of existing simulations models. In this review, we introduce the non-expert reader to coarse-grained membrane simulations at the mesoscale. Firstly, we give a concise overview of the modelling approaches to study fluid membranes, together with guidance to more specialized references. Secondly, we provide a conceptual guide on how to develop mesoscale membrane simulations. Lastly, we construct a hands-on tutorial on how to apply mesoscale membrane simulations, by providing a pedagogical examination of membrane tether pulling, shape and mechanics of membrane tubes, and membrane fluctuations with three different membrane models, and discussing them in terms of their scope and how resource-intensive they are. To ease the reader's venture into the field, we provide a repository with ready-to-run tutorials.}, author = {Muñoz Basagoiti, Maitane and Frey, Felix F and Meadowcroft, Billie and Santana de Freitas Amaral, Miguel and Prada, Adam and Šarić, Anđela}, issn = {1744-6848}, journal = {Soft Matter}, number = {40}, pages = {7736--7756}, publisher = {Royal Society of Chemistry}, title = {{A tutorial for mesoscale computer simulations of lipid membranes: Tether pulling, tubulation and fluctuations}}, doi = {10.1039/d5sm00148j}, volume = {21}, year = {2025}, } @article{21251, abstract = {Cellular membranes differ across the tree of life. In most bacteria and eukaryotes, single-headed lipids self-assemble into flexible bilayer membranes. By contrast, thermophilic archaea tend to possess bilayer lipids together with double-headed, monolayer spanning bolalipids, which are thought to enable cells to survive in harsh environments. Here, using a minimal computational model for bolalipid membranes, we explore the trade-offs at play when forming membranes. We find that flexible bolalipids form membranes that resemble bilayer membranes because they are able to assume a U-shaped conformation. Conversely, rigid bolalipids, which resemble the bolalipids with cyclic groups found in thermophilic archaea, take on a straight conformation and form membranes that are stiff and prone to pore formation when they undergo changes in shape. Strikingly, however, the inclusion of small amounts of bilayer lipids in a bolalipid membrane is enough to achieve fluid bolalipid membranes that are both stable and flexible, resolving this trade-off. Our study suggests a mechanism by which archaea can tune the material properties of their membranes as and when required to enable them to survive in harsh environments and to undergo essential membrane remodelling events like cell division.}, author = {Santana de Freitas Amaral, Miguel and Frey, Felix F and Jiang, Xiuyun and Baum, Buzz and Šarić, Anđela}, issn = {2050-084X}, journal = {eLife}, publisher = {eLife Sciences Publications}, title = {{Balancing stability and flexibility when reshaping archaeal membranes}}, doi = {10.7554/elife.105432}, volume = {14}, year = {2025}, } @article{18526, abstract = {Multivesicular endosomes (MVEs) sequester membrane proteins destined for degradation within intralumenal vesicles (ILVs), a process mediated by the membrane-remodeling action of Endosomal Sorting Complex Required for Transport (ESCRT) proteins. In Arabidopsis, endosomal membrane constriction and scission are uncoupled, resulting in the formation of extensive concatenated ILV networks and enhancing cargo sequestration efficiency. Here, we used a combination of electron tomography, computer simulations, and mathematical modeling to address the questions of when concatenated ILV networks evolved in plants and what drives their formation. Through morphometric analyses of tomographic reconstructions of endosomes across yeast, algae, and various land plants, we have found that ILV concatenation is widespread within plant species, but only prevalent in seed plants, especially in flowering plants. Multiple budding sites that require the formation of pores in the limiting membrane were only identified in hornworts and seed plants, suggesting that this mechanism has evolved independently in both plant lineages. To identify the conditions under which these multiple budding sites can arise, we used particle-based molecular dynamics simulations and found that changes in ESCRT filament properties, such as filament curvature and membrane binding energy, can generate the membrane shapes observed in multiple budding sites. To understand the relationship between membrane budding activity and ILV network topology, we performed computational simulations and identified a set of membrane remodeling parameters that can recapitulate our tomographic datasets.}, author = {Weiner, Ethan and Berryman, Elizabeth and Frey, Felix F and Solís, Ariadna González and Leier, André and Lago, Tatiana Marquez and Šarić, Anđela and Otegui, Marisa S.}, issn = {1091-6490}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, number = {44}, publisher = {National Academy of Sciences}, title = {{Endosomal membrane budding patterns in plants}}, doi = {10.1073/pnas.2409407121}, volume = {121}, year = {2024}, } @article{18704, abstract = {Clathrin-mediated endocytosis is the main pathway used by eukaryotic cells to take up extracellular material, but the dominant physical mechanisms driving this process are still elusive. Recently, several high-resolution imaging techniques have been used on different cell lines to measure the geometrical properties of clathrin-coated pits over their whole lifetime. Here, we first show that the combination of all datasets with the recently introduced cooperative curvature model defines a consensus pathway, which is characterized by a flat-to-curved transition at finite area, followed by linear growth and subsequent saturation of curvature. We then apply an energetic model for the composite of the plasma membrane and clathrin coat to this consensus pathway to show that the dominant mechanism for invagination could be coat stiffening, which might originate from cooperative interactions between the different clathrin molecules and progressively drives the system toward its intrinsic curvature. Our theory predicts that two length scales determine the invagination pathway, namely the patch size at which the flat-to-curved transition occurs and the final pit radius.}, author = {Frey, Felix F and Schwarz, Ulrich S.}, issn = {2470-0053}, journal = {Physical Review E}, number = {6}, publisher = {American Physical Society}, title = {{Coat stiffening can explain invagination of clathrin-coated membranes}}, doi = {10.1103/PhysRevE.110.064403}, volume = {110}, year = {2024}, } @unpublished{18670, abstract = {Across the tree of life, distinct designs of cellular membranes have evolved. In bacteria and eukaryotes single-headed lipids self-assemble into flexible bilayer membranes. By contrast, archaea often possess double-headed, monolayer spanning bolalipids, mixed with bilayer lipids, enabling them to survive in harsh environments. Here, using a minimal computational model for bolalipid membranes, we discover trade-offs when forming membranes. We find that membranes made out of flexible bolalipids resemble bilayer membranes as bolalipids exhibit conformational switch into U-shaped conformations to enable higher curvatures. Conversely, stiffer bolalipids, resembling those in extremophile archaea, take on straight conformations and form liquid membranes that are stiff, and prone to pore formation during membrane reshaping. Strikingly, we show how to achieve fluid bolalipid membranes that are both stable and flexible – by including small amounts of bilayer lipids, as archaea do. Our study explains how different organisms resolve trade-offs when generating membranes of desired material properties.}, author = {Santana de Freitas Amaral, Miguel and Frey, Felix F and Jiang, Xiuyun and Baum, Buzz and Šarić, Anđela}, booktitle = {bioRxiv}, title = {{Stability vs flexibility: Reshaping archaeal membranes in silico}}, doi = {10.1101/2024.10.18.619072}, year = {2024}, } @article{14782, abstract = {The actin cortex is a complex cytoskeletal machinery that drives and responds to changes in cell shape. It must generate or adapt to plasma membrane curvature to facilitate diverse functions such as cell division, migration, and phagocytosis. Due to the complex molecular makeup of the actin cortex, it remains unclear whether actin networks are inherently able to sense and generate membrane curvature, or whether they rely on their diverse binding partners to accomplish this. Here, we show that curvature sensing is an inherent capability of branched actin networks nucleated by Arp2/3 and VCA. We develop a robust method to encapsulate actin inside giant unilamellar vesicles (GUVs) and assemble an actin cortex at the inner surface of the GUV membrane. We show that actin forms a uniform and thin cortical layer when present at high concentration and distinct patches associated with negative membrane curvature at low concentration. Serendipitously, we find that the GUV production method also produces dumbbell-shaped GUVs, which we explain using mathematical modeling in terms of membrane hemifusion of nested GUVs. We find that branched actin networks preferentially assemble at the neck of the dumbbells, which possess a micrometer-range convex curvature comparable with the curvature of the actin patches found in spherical GUVs. Minimal branched actin networks can thus sense membrane curvature, which may help mammalian cells to robustly recruit actin to curved membranes to facilitate diverse cellular functions such as cytokinesis and migration.}, author = {Baldauf, Lucia and Frey, Felix F and Arribas Perez, Marcos and Idema, Timon and Koenderink, Gijsje H.}, issn = {0006-3495}, journal = {Biophysical Journal}, keywords = {Biophysics}, number = {11}, pages = {2311--2324}, publisher = {Elsevier}, title = {{Branched actin cortices reconstituted in vesicles sense membrane curvature}}, doi = {10.1016/j.bpj.2023.02.018}, volume = {122}, year = {2023}, } @article{14788, abstract = {Eukaryotic cells use clathrin-mediated endocytosis to take up a large range of extracellular cargo. During endocytosis, a clathrin coat forms on the plasma membrane, but it remains controversial when and how it is remodeled into a spherical vesicle. Here, we use 3D superresolution microscopy to determine the precise geometry of the clathrin coat at large numbers of endocytic sites. Through pseudo-temporal sorting, we determine the average trajectory of clathrin remodeling during endocytosis. We find that clathrin coats assemble first on flat membranes to 50% of the coat area before they become rapidly and continuously bent, and this mechanism is confirmed in three cell lines. We introduce the cooperative curvature model, which is based on positive feedback for curvature generation. It accurately describes the measured shapes and dynamics of the clathrin coat and could represent a general mechanism for clathrin coat remodeling on the plasma membrane.}, author = {Mund, Markus and Tschanz, Aline and Wu, Yu-Le and Frey, Felix F and Mehl, Johanna L. and Kaksonen, Marko and Avinoam, Ori and Schwarz, Ulrich S. and Ries, Jonas}, issn = {1540-8140}, journal = {Journal of Cell Biology}, keywords = {Cell Biology}, number = {3}, publisher = {Rockefeller University Press}, title = {{Clathrin coats partially preassemble and subsequently bend during endocytosis}}, doi = {10.1083/jcb.202206038}, volume = {222}, year = {2023}, }