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Role of lipids in spheroidal high density lipoproteins.

Vuorela T, Catte A, Niemelä PS, Hall A, Hyvönen MT, Marrink SJ, Karttunen M, Vattulainen I - PLoS Comput. Biol. (2010)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Physics, Tampere University of Technology, Tampere, Finland.

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.

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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.
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pcbi-1000964-g010: 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.

Mentions: The sterol ring of CHOL molecules can intercalate or interact with the aromatic side chains of protein residues as observed for CE in a recent study by Catte et al. [36]. This interaction between CHOL molecules and apoA-I was also observed experimentally by Dergunov et al. [64]. The authors estimated the degree of exclusion of CHOL molecules from the boundary lipid region in reconstituted discoidal HDL particles containing different apolipoproteins and observed an increase in the order A-I<E<A-II. The partial exclusion of CHOL molecules operated by apoA-I and the corresponding CHOL distribution among surface and bulk lipids are in good agreement with our findings as depicted through a series of snapshots in Figure 10 (see also SI).


Role of lipids in spheroidal high density lipoproteins.

Vuorela T, Catte A, Niemelä PS, Hall A, Hyvönen MT, Marrink SJ, Karttunen M, Vattulainen I - PLoS Comput. Biol. (2010)

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.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2965744&req=5

pcbi-1000964-g010: 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.
Mentions: The sterol ring of CHOL molecules can intercalate or interact with the aromatic side chains of protein residues as observed for CE in a recent study by Catte et al. [36]. This interaction between CHOL molecules and apoA-I was also observed experimentally by Dergunov et al. [64]. The authors estimated the degree of exclusion of CHOL molecules from the boundary lipid region in reconstituted discoidal HDL particles containing different apolipoproteins and observed an increase in the order A-I<E<A-II. The partial exclusion of CHOL molecules operated by apoA-I and the corresponding CHOL distribution among surface and bulk lipids are in good agreement with our findings as depicted through a series of snapshots in Figure 10 (see also SI).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Physics, Tampere University of Technology, Tampere, Finland.

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.

Show MeSH