Subdomains of Endophilin-NBAR Can Synergistically Drive Membrane Remodeling and Facilitate Controlled Membrane Scission

The NBAR-domain containing protein endophilin, as a major player in many endocytic pathways, has offered considerable insight into BAR-domain driven membrane remodeling. However, understanding the interaction of the different subdomains of endophilin and their abilities to sense and generate negative Gaussian curvature are yet unanswered questions, with significant implications for the mechanisms and regulation of unconventional endocytic pathways. Using coarse-grained molecular dynamics simulation, we demonstrate the synergistic remodeling capabilities of the NBAR remodeling unit, as well as its ability to sort to and generate membrane regions with negative Gaussian curvature. We find that the assembly of NBAR scaffolds at regions of negative Gaussian curvature facilitate membrane hemifission in dynamic bud formation. These insights provide an additional role for endophilin scaffolds in endocytosis, as well as emphasizing the importance of developing new ways to study negative Gaussian curvature. STATEMENT OF SIGNIFICANCEThis work provides deeper insight into the composite membrane remodeling abilities of NBAR domains in peripheral membrane proteins and their sorting to negative Gaussian curvature. Theis work also explicitly models at the molecular level the {Omega}-shaped membrane geometry, connecting endophilin mechanics to its physiological function in endocytosis.