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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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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.
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pcbi-1000964-g004: 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.

Mentions: To start with, one gets an impression that the density plot adheres to the two-layer model [6], [7], [22] wherein one assumes almost full separation of hydrophilic and hydrophobic molecules into two separate regions. While the distribution of TG fits into this picture, the distribution of CE and CHOL does not. A rather significant amount of CHOL is also in the core of the particle as was discussed above. Detailed consideration further reveals that there is a significant overlap of CE with CHOL, POPC, and PPC: The radial density distributions shown in Figure 3 do not provide a sufficiently unique description of only two different structural regions inside HDL. Furthermore, by looking at the order parameters of CHOL and CE presented in Figure 4 it becomes evident that there are not only two regions but also the intermediate one between the hydrophobic and hydrophilic ones. The innermost core of the particle ( nm) is clear, as there the ring structures of both CHOL and CE are oriented in a completely random fashion. The situation changes as one approaches the lipid-water interface through the intermediate region (3 nm nm), which is characterized by significant ordering of the ring structures, in a manner where the principal axis of CE's and CHOL's ring moiety lies along the radial direction of HDL. This intermediate region overlaps with the distribution of the acyl chains of POPC and PPC, revealing that the sterol rings are also aligned with the acyl chains. Finally, at the HDL-water interface, one finds the region composed of hydrophilic headgroups of POPC and PPC that constitute the surface part of the lipid droplet interacting mostly with water.


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)

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.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1000964-g004: 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.
Mentions: To start with, one gets an impression that the density plot adheres to the two-layer model [6], [7], [22] wherein one assumes almost full separation of hydrophilic and hydrophobic molecules into two separate regions. While the distribution of TG fits into this picture, the distribution of CE and CHOL does not. A rather significant amount of CHOL is also in the core of the particle as was discussed above. Detailed consideration further reveals that there is a significant overlap of CE with CHOL, POPC, and PPC: The radial density distributions shown in Figure 3 do not provide a sufficiently unique description of only two different structural regions inside HDL. Furthermore, by looking at the order parameters of CHOL and CE presented in Figure 4 it becomes evident that there are not only two regions but also the intermediate one between the hydrophobic and hydrophilic ones. The innermost core of the particle ( nm) is clear, as there the ring structures of both CHOL and CE are oriented in a completely random fashion. The situation changes as one approaches the lipid-water interface through the intermediate region (3 nm nm), which is characterized by significant ordering of the ring structures, in a manner where the principal axis of CE's and CHOL's ring moiety lies along the radial direction of HDL. This intermediate region overlaps with the distribution of the acyl chains of POPC and PPC, revealing that the sterol rings are also aligned with the acyl chains. Finally, at the HDL-water interface, one finds the region composed of hydrophilic headgroups of POPC and PPC that constitute the surface part of the lipid droplet interacting mostly with water.

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