How Synaptotagmin I, N-BAR and F-BAR Domains Generate Membrane Curvature

Protein-induced membrane curving governs many cellular processes, including cell division, growth and cell-cell communication. In order to unravel the mechanism for how membrane curvature occurs driven by the proteins, one needs to have detailed molecular pictures on the key membrane-protein interactions and protein-protein interactions. Computer simulation serves as a great tool in providing such molecular pictures and thus in rationalizing how proteins curve membrane. For example, it is known that neurotransmitter release involves a Ca++ ion-regulated fusion process between synaptic vesicles and the presynaptic membrane, but little is known for how such small ions function. With the help of computer simulation, we realized the Ca++-sensor protein, synaptotagmin I, undergoes a conformational transition after binding to both the Ca++ and membrane that differs from the membrane-free crystal/NMR structure. The new synaptotagmin conformation has its C-terminal helix to interact with the presynaptic membrane, and thereby, causes the presynaptic membrane to curve and facilitates membrane-vesicle fusion. Another example in showing the power of computer simulation lies in resolving how N-BAR and F-BAR domains sculpt a flat membrane. As these domains form a lattice in the sculpting process, we identified the optimal lattice type and key protein-protein interactions within the lattice. The whole process of membrane tubulation from a flat membrane was resolved from the simulations, and agreements were found between the lattice structures observed via cryo-electron microscopy and the simulations.