Hierarchical coarse-graining strategy for protein-membrane systems to access mesoscopic scales

Abstract

An overall multiscale simulation strategy for large scale coarse-grain simulations of membrane protein systems is presented. The protein is modeled as a heterogeneous elastic network, while the lipids are modeled using the hybrid analytic-systematic (HAS) methodology, where in both cases atomistic level information obtained from molecular dynamics simulation is used to parameterize the model. A feature of this approach is that from the outset liposome length scales are employed in the simulation (i.e., on the order of 1/2 a million lipids plus protein). A route to develop highly coarse-grained models from molecular-scale information is proposed and results for N-BAR domain protein remodeling of a liposome are presented.

Fig. 1

The CG model used in the ED-BAR-liposome simulation. Part (a) shows the hetero-ENM model of the ED-BAR domain as derived from the fully atomistic representation. The two amphipathic helices (highlighted by blue spheres in the left panel) are modeled by two additional sites, as shown in the right panel image. Part (b) depicts the HAS CG lipid model. The fully atomistic lipid is modeled as a single site GB ellipsoid of revolution, augmented with a radially symmetric MS-CG interaction. See ref. for more details. An additional head-group site interacts with the ED-BAR domain, but does not alter the total lipid–lipid interaction.

Fig. 2

The potential of mean force (PMF) obtained from the distribution function for the distance between the phosphorus atom in the lipid headgroups to the center of mass of the positively charged residues underneath the BAR domain.

Fig. 3

Analysis of the ED-BAR density, mean curvature, H, and relative membrane density change, δρ/ρ₀, in the remodeled and isolated liposomes. The original system is a snapshot of the ED-BAR coated liposome. The local ED-BAR density shows local ED-BAR enhancements and depletions that are correlated with both the mean curvature and membrane density. The yellow squares highlight regions where the correlations are most clearly visible. The lower panel on the right shows corresponding plots for the isolated liposome. The scale bar at the bottom gives the reference for each color in the upper panels. The inset at the lower left plots the mean curvature versus liposome density for the two systems. Purple is for the isolated liposome while cyan shows how the local mean curvature is enhanced and distorted because of the ED-BAR membrane remodeling. The upper values of the mean induced curvature correspond to those observed from MD simulations (i.e., about half that observed from MD simulation of a single N-BAR domain, since the mean curvature is the average over two principle curvatures and the single N-BAR domain induces curvature in only one direction).

Fig. 4

Selected close-up snapshots of the remodeled liposome, obtained by rotating the liposome and selecting out specific regions. The square boxes highlight specific remodeled regions of interest: (a) shows a double hump, (b) a large curved region where the embedded helix sites are visible, (c) a tightly bent region with a high density of ED-BARs on the surface, and (d) a relatively flat region with a correspondingly low ED-BAR density in that region.