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N-BAR domains are protein modules that bind to and induce curvature in membranes via a charged concave surface and N-terminal amphipathic helices. Recently, molecular dynamics simulations have demonstrated that the N-BAR domain can induce a strong local curvature that matches the curvature of the BAR domain surface facing the bilayer. Here we present further molecular dynamics simulations that examine in greater detail the roles of the concave surface and amphipathic helices in driving local membrane curvature. We find that the strong curvature induction observed in our previous simulations requires the stable presentation of the charged concave surface to the membrane and is not driven by the membrane-embedded amphipathic helices. Nevertheless, without these amphipathic helices embedded in the membrane, the N-BAR domain does not maintain a close association with the bilayer, and fails to drive membrane curvature. Increasing the membrane negative charge through the addition of PIP(2) facilitates closer association with the membrane in the absence of embedded helices. At sufficiently high concentrations, amphipathic helices embedded in the membrane drive membrane curvature independently of the BAR domain.

Liposome remodeling processes (e.g., vesiculation and tubulation) due to N-BAR domain interactions with the lipid bilayer are explored with a multi-scale simulation approach. Results from atomistic-level molecular dynamics simulations of membrane binding to the concave face of N-BAR domains are used along with discretized mesoscopic field-theoretic simulations to examine how the spontaneous curvature fields generated by N-BAR domains result in membrane remodeling. It is found that tubulation can be generated by anisotropic N-BAR spontaneous curvature fields, whereas vesiculation is only observed with isotropic N-BAR spontaneous curvature fields at high density. The results of the multi-scale simulations provide insight into recent experimental observations.