Membrane Sculpting by F-BAR Domains Studied by Molecular Dynamics Simulations

Interplay between cellular membranes and their peripheral proteins drives many processes in eukaryotic cells. Proteins of the Bin/Amphiphysin/Rvs (BAR) domain family, in particular, play a role in cellular morphogenesis, for example curving planar membranes into tubular membranes. However, it is still unclear how F-BAR domain proteins act on membranes. Electron microscopy revealed that, in vitro, F-BAR proteins form regular lattices on cylindrically deformed membrane surfaces. Using all-atom and coarse-grained (CG) molecular dynamics simulations, we show that such lattices, indeed, induce tubes of observed radii. A 250 ns all-atom simulation reveals that F-BAR domain curves membranes via the so-called scaffolding mechanism. Plasticity of the F-BAR domain permits conformational change in response to membrane interaction, via partial unwinding of the domains 3-helix bundle structure. A CG simulation covering more than 350 µs provides a dynamic picture of membrane tubulation by lattices of F-BAR domains. A series of CG simulations identified the optimal lattice type for membrane sculpting, which matches closely the lattices seen through cryo-electron microscopy. Author Summary: To generate organelles, eukaryotic cells sculpt their membranes into compartments, often employing proteins as chaperones, for example, F-BAR domains. The latter induce formation of tubular and vesicular membranes. Functional and structural studies suggest that F-BAR domains sculpt membranes through electrostatic interactions, driving the membrane to match the concave surface of the protein's banana-like shape. Cryo-electron microscopy (cryo-EM) studies provide an average static picture of how F-BAR domains form lattices on the surface of membranes to induce tube formation. Complementing the cryo-EM images, molecular dynamics simulations reported here offer a detailed, dynamic picture of membrane tubulation by a lattice of F-BAR domains and identified lattice types optimally attuned to producing high membrane curvature. The simulations reproduced also a process lasting 350 µs in which lattices of F-BAR domains form a complete tube out of an initially flat membrane. The molecular dynamics study offers, thereby, both a large-scale picture of membrane sculpting by F-BAR domain lattices as well as atomic-level dynamic information about the involvement of the individual F-BAR domain and its interactions with partner F-BAR domains and membrane in the sculpting process.