Molecular Simulation and Continuum Modeling of N-Bar-Induced Lipid Membrane Deformations

Abstract

The N-terminal BAR (N-BAR) domain is a banana-shaped homo-dimer capable of sensing and enforcing its concave shape on a lipid membrane by a “scaffolding” mechanism. N-BAR domains are known to induce tubulation in vivo via scaffolding curvature and likely act cooperatively to bend large lipid areas. These mesoscopic and mesotemporal phenomena are difficult to directly study using molecular dynamics simulations, and experiments cannot directly describe the curvature mechanism. Therefore, the long-term goal of this study is to develop a model of the N-BAR domain suitable for use in continuum Helfrich-Canham modeling that can quantify the mesoscale bending mechanism. We begin with a set of all-atom molecular dynamics simulations to describe the mean deformation profile caused by a single N-BAR. While generating this profile, we track curvature-sensitive lipids along the deformation profile and check for redistribution according to their spontaneous (intrinsic) curvatures. This type of redistribution is typically difficult to quantify, but is likely to impact the protein's effect on the lipid membrane -- making it harder or easier to maintain induced curvature. We demonstrate a method to fit the induced deformation to a surface and then map lipid densities onto the calculated surface. Data from the fitted induced curvature profiles and resulting lipid redistribution are piped into a continuum model that recapitulates the molecular dynamics results. Building up the continuum model using first principles allows simulation of many N-BAR domains on large lipid patches, allowing us to observe tubulation events in silico.