BPS2026 – Building a model of membrane reshaping from highly curved non-lamellar lipid structures

Energetic barriers and intermediates in membrane fission and fusion are typically highly curved. Building a model of these highly curved bilayer regions requires understanding how local lipid composition and interactions adapt to stabilize such a structure. To extract this information, molecular simulations can apply special highly curved, frequently non-lamellar structures that model high-energy sites in intermediates in membrane reshaping. The lipid inverse hexagonal phase, available to both simulation and experiment, allows direct observation of a single highly curved lipidic leaflet. With appropriate boundary conditions (equivalent to external forces), single-bilayer pores and edges can be modeled at equilibrium. Microsecond-scale simulations of toroidal fusion/fission pores and hemifusion diaphragms allow for observations of how modeled lipids redistribute and change their interactions on structures directly modeling reshaping intermediates. Here, mechanical analysis, dynamic lipid redistribution, and alchemical free-energy perturbation methodology will be applied to extract the model energetics of simulated lipids on these highly curved structures.