Conical lipids in flat bilayers induce packing defects similar to that induced by positive curvature

Abstract

In biological membranes, changes in lipid composition or mechanical deformations produce defects in the geometrical arrangement of lipids, thus allowing the adsorption of certain peripheral proteins. Here, we perform molecular dynamics simulations on bilayers containing a cylindrical lipid (PC) and a conical lipid (DOG). Profiles of atomic density and lateral pressure across the bilayer show differences in the acyl chain region due to deeper partitioning of DOG compared to PC. However, such analyses are less informative for the interfacial region where peripheral proteins adsorb. To circumvent this limitation, we develop, to our knowledge, a new method of membrane surface analysis. This method allows the identification of chemical defects, where hydrocarbon chains are accessible to the solvent, and geometrical defects, i.e., voids deeper than the glycerol backbone. The size and number of both types of defects increase with the number of monounsaturated acyl chains in PC and with the introduction of DOG, although the defects do not colocalize with the conical lipid. Interestingly, the size and probability of the defects promoted by DOG resemble those induced by positive curvature, thus explaining why conical lipids and positive curvature can both drive the adsorption of peripheral proteins that use hydrophobic residues as membrane anchors.

Figure 1

Structure of DOPC and DOG. Note that the double bond on each aliphatic tail is in a cis configuration. Each label below the phosphorous atom applies for both DOPC and DOG and for each aliphatic chain (sn-1 and sn-2).

Figure 2

Cross-section analysis of DOPC/DOG and DOPC bilayers. The upper panels show snapshots of DOPC/DOG (85:15 mol:mol) (a) and pure DOPC (b) bilayers. All atoms are represented as wireframes except C2 atoms of DOPC and DOG, which are depicted as gray (DOPC) or red (DOG) spheres. The middle panels show density profiles for DOPC/DOG (c) and DOPC (d) bilayers with the density of the whole system in black, DOPC in gray, DOG in red, and water in blue. The vertical dotted lines coincide with the C2 carbons of DOPC (gray) and DOG (red); the vertical solid line corresponds to the center of the bilayer. The lower panels show the symmetrized lateral pressure profile (with error bars) of DOPC/DOG (e) and DOPC (f) bilayers. The vertical lines indicate the bilayer center as well as the C2 atoms of DOPC and DOG. Note that the density and pressure profiles indicate substantial changes between the two bilayers for the hydrophobic region but not for the polar region.

Figure 3

Potentials of mean force for transferring the headgroup of DOPC and DOG from water to the center of a pure DOPC or DOPC/DOG bilayer. For each PMF, the position restraint was placed on the hydroxyl or phosphate of the headgroup (for DOG and DOPC, respectively) and used to determine the x axis. The PMFs are shown with error bars.

Figure 4

Detection of lipid packing defects. The three methods to identify packing defects in the interfacial zone of model membranes are schematized in the top row. The other panels show snapshots of the surface of DOPC/DOG and DMPC bilayers with polar heads in gray and aliphatic carbon atoms in yellow. For each composition, the columns are arranged as follows: (a) the pure bilayer; (b) the bilayer with the packing defects (blue) computed with the ASA method; (c and d) the bilayer with the chemical (c) or geometrical (d) defects (blue) computed with our new Cartesian scheme. The ASA method uses of a probe of 0.3 nm in radius and maps the accessible aliphatic carbon atoms. The Cartesian schemes probe the bilayer vertically by squares of 0.01 nm² and look for all accessible aliphatic carbon atoms (chemical defects) or only those that are below the glycerol level (geometrical defects). See text for further details.

Figure 5

Size distribution of packing defects in model membrane systems. The various plots show the probability of finding a defect of defined size as obtained by the ASA method (a; like in (25)) or by the Cartesian schemes for geometrical (b) or chemical (c) defects. The color code is as follows: green, DMPC; blue, POPC; black, DOPC; red, DOPC/DOG. Each solid line is a fit to an exponential distribution for defects larger than 0.05 nm² and with probability ≥10⁻⁴. The fits give the following decay constants (in units of nm⁻²) for DMPC, POPC, DOPC, and DOPC/DOG, respectively: (a) 13.1, 12.1, 9.0, and 7.7; (b) 14.6, 12.4, 11.5, and 10.8; (c) 8.8, 6.7, 5.3, and 4.7. The decay constants obtained in panel (a) are plotted in panel (d) and compared to those obtained by Cui et al. (25) on a DOPC/DOPS patch either in a flat or in a convex conformation.