Role of lipids in spheroidal high density lipoproteins

Abstract

We study the structure and dynamics of spherical high density lipoprotein (HDL) particles through coarse-grained multi-microsecond molecular dynamics simulations. We simulate both a lipid droplet without the apolipoprotein A-I (apoA-I) and the full HDL particle including two apoA-I molecules surrounding the lipid compartment. The present models are the first ones among computational studies where the size and lipid composition of HDL are realistic, corresponding to human serum HDL. We focus on the role of lipids in HDL structure and dynamics. Particular attention is paid to the assembly of lipids and the influence of lipid-protein interactions on HDL properties. We find that the properties of lipids depend significantly on their location in the particle (core, intermediate region, surface). Unlike the hydrophobic core, the intermediate and surface regions are characterized by prominent conformational lipid order. Yet, not only the conformations but also the dynamics of lipids are found to be distinctly different in the different regions of HDL, highlighting the importance of dynamics in considering the functionalization of HDL. The structure of the lipid droplet close to the HDL-water interface is altered by the presence of apoA-Is, with most prominent changes being observed for cholesterol and polar lipids. For cholesterol, slow trafficking between the surface layer and the regimes underneath is observed. The lipid-protein interactions are strongest for cholesterol, in particular its interaction with hydrophobic residues of apoA-I. Our results reveal that not only hydrophobicity but also conformational entropy of the molecules are the driving forces in the formation of HDL structure. The results provide the first detailed structural model for HDL and its dynamics with and without apoA-I, and indicate how the interplay and competition between entropy and detailed interactions may be used in nanoparticle and drug design through self-assembly.

Figure 1. Descriptions of the molecules considered in the study.

(Top) Atomistic (united atom) descriptions, and (bottom) the coarse-grained representations.

Figure 2. Example of a protein-free lipid droplet (left), its molecular distribution shown through a slice across the particle (middle), and HDL including two apoA-I proteins (right).

Dark gray stands for POPC headgroup and dark brown for PPC headgroups, light gray for POPC hydrocarbon chains, light brown for PPC chains, light orange for CHOL OH-groups, bright yellow for cholesterol body, dark orange for CE ester bond, orange for CE ester body and chain, dark green for TG ester bonds, and bright green for TG chain. In HDL, proline residues in apoA-I sequences are in green.

Figure 3. Radial densities showing the composition of the studied particles versus distance from the center of mass (COM) of the particle.

The solid lines are for the full HDL particle, the dashed lines for the lipid droplet without apoA-I.

Figure 4. Order parameter for the ring structures of CHOL (left) and CE (right).

The black curves describe the lipid droplet and the red curves the full HDL.

Figure 5. Distributions of CE conformations.

The horizontal axis is the angle between the CE ring and the effective normal of the lipid droplet. The vertical axis is the angle between the ring structure and the oleate chain. The left panels (A, C) describe the core of the droplet ( nm) and the right panels (B, D) the surface ( nm). The pictures at the top (A, B) show the lipid droplet without apoA-I and those at the bottom (C, D) the full HDL.

Figure 6. Diffusion coefficients of the lipid components.

Each point in the plot describes the diffusion coefficient for one of the lipid types. The distance is the average distance of the given lipid from the COM of the particle. To facilitate comparison between core (three-dimensional diffusion) and surface lipids (two-dimensional diffusion), the coefficients have been scaled with , where is the dimension of the fit (either two or three).

Figure 7. Root mean square fluctuation (RMSF) profiles for apoA-I alpha carbons (black, chain A; red, chain B) measured over the last 4 s of the simulation of the full HDL particle.

Experiments suggest that the alpha-helical region is likely given by the residues 44–241, and that the alpha-helical content overall is about 75–80% , , , .

Figure 8. Number of annular lipid molecules over the last 4 s of the simulation of the full HDL particle: POPC (blue), CHOL (red), CE (orange), PPC (purple) and TG (green).

Figure 9. Number of contacts of CHOL molecules with apoA-I residues normalized per residue.

See text for details. Isoleucine and cysteine are absent in the human apoA-I sequence considered here .

Figure 10. Illustrative snapshots of HDL structure.

(Top) Different snapshots of the full HDL simulation: (A) 0 s, (B) 0.4 s, (C) 1.4 s, (D) 12.4 s, and (E) 19.04 s. (Bottom) Snapshots displayed at the top of the figure showing here only the apoA-I molecules, and annular and bulk CHOL molecules. The two apoA-I chains are in light red (chain A) and light blue (chain B) with proline residues in green. Annular CHOL molecules are shown in purple with a dark red hydroxyl group. Bulk CHOL molecules are depicted in yellow with an orange hydroxyl group.