Multiscale simulation of protein mediated membrane remodeling

Abstract

Proteins interacting with membranes can result in substantial membrane deformations and curvatures. This effect is known in its broadest terms as membrane remodeling. This review article will survey current multiscale simulation methodologies that have been employed to examine protein mediated membrane remodeling.

Figure 1

A schematic of the multiscale characteristics of protein mediated membrane remodeling. Images (a-1) to (a-3), (b-1) to (b-4), and then (c-1) and (c-2) give simulation snapshots of N-BAR domain driven membrane remodeling at the atomic, CG, and mesoscopic scales, respectively. The colored arrows designate different multiscale paths where by the simulations can ultimately connect with EM imaging (EM image (d) of amphiphysin tubulation courtesy of V. Unger). Path (1) connects image (a-1), the atomic level, with (b-1) the CG scale. In this path, lipids (a-2) and proteins (a-3) are systematically coarse-grained into much simpler objects (b-2) and (b-3), but still retain residual atomic-level information. An entire 200 nm diameter liposome composed of around half a million CG lipids undergoing the early stages of remodeling is shown in image (b-1). Path (2) directly connects the atomic with the mesoscopic scale, and is a methodology sometimes employed. This path requires fairly extensive phenomenological information. However, as path (2) connects to image (c-1) and (c-2), the mesoscopic representation, liposome remodeling of 500 nm diameter liposomes can be described over effectively very long (macroscopic) timescales. It is at this end point that direct comparisons with EM imaging can be achieved (image d). The two different mesoscopic images, (c-1) and (c-2), give an indication of the polymorphism of structures that can be generated depending on relatively small variations in the N-BAR oligomerization energy, and when compared to the ensemble of real experimental images that can occur in image (d), further demonstrates how complex the protein-mediated membrane remodeling process can be. The multiscale path (3) connects the atomistic scale to the mesoscopic scale via an intermediate CG simulation scale. Here, long length-scale correlations of entire N-BAR domains (as in image (b-1)) systematically guide the development of mesoscopic models that then do not have to rely on phenomenological information. The lower inset, image (b-4) shows a close-up cut-away of image (b-1), the CG scale, where the membrane is becoming remodeled by CG N-BAR domains embedding amphipathic helices into the low density regions of the outer CG bilayer.