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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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Descriptions of the molecules considered in the study.(Top) Atomistic (united atom) descriptions, and (bottom) the coarse-grained representations.
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pcbi-1000964-g001: Descriptions of the molecules considered in the study.(Top) Atomistic (united atom) descriptions, and (bottom) the coarse-grained representations.

Mentions: Our objective is to overcome the above limitations. We have performed MD simulations of spheroidal HDL particles using the full lipid composition of human plasma HDL [19]. Instead of atom-scale simulations, we employ the coarse-grained MARTINI model [39], [40] that has performed exceptionally well in a number of studies dealing with lipids and proteins [36], [39]–[42]. We consider both the protein-free lipid droplets and the full HDL particles containing also two apoA-I molecules around the droplet, see Figures 1 and 2. Composition of the HDL system is described in Table 1 with abbreviations of all molecules included. By comparing the protein-free and the full HDL models, we can clarify the role of lipids and proteins in HDL. The principal objective is to fill the gap of detailed structural and dynamic information of lipids in spheroidal HDL particles. We also address questions related to the role of apoA-I proteins and their interactions with lipids in HDL structures. The currently incomplete understanding of the latter issue is largely due to the size heterogeneity of HDLs (diameters range from 7.2 () to 12 nm ()) and the large flexibility of apoA-I. The latter renders the prediction of the positioning of different alpha helices of apoA-I on a spherical surface very difficult. The distribution of lipids inside HDL and their interplay with apoA-I are of profound interest. From a more general perspective, knowledge of the structure of spheroidal HDL is crucial for understanding the conformational changes when HDL makes the transition from discoidal to spheroidal shape, and the trafficking of CHOL and CE through the action of cholesteryl ester transfer protein [43]. Additionally, to design nanoparticles with desired surface and bulk properties, e.g., for controlled transport and release of drugs and contrast agents, it is vital to understand the conformational changes as well as the underlying mechanisms in detail [44]–[51].


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)

Descriptions of the molecules considered in the study.(Top) Atomistic (united atom) descriptions, and (bottom) the coarse-grained representations.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1000964-g001: Descriptions of the molecules considered in the study.(Top) Atomistic (united atom) descriptions, and (bottom) the coarse-grained representations.
Mentions: Our objective is to overcome the above limitations. We have performed MD simulations of spheroidal HDL particles using the full lipid composition of human plasma HDL [19]. Instead of atom-scale simulations, we employ the coarse-grained MARTINI model [39], [40] that has performed exceptionally well in a number of studies dealing with lipids and proteins [36], [39]–[42]. We consider both the protein-free lipid droplets and the full HDL particles containing also two apoA-I molecules around the droplet, see Figures 1 and 2. Composition of the HDL system is described in Table 1 with abbreviations of all molecules included. By comparing the protein-free and the full HDL models, we can clarify the role of lipids and proteins in HDL. The principal objective is to fill the gap of detailed structural and dynamic information of lipids in spheroidal HDL particles. We also address questions related to the role of apoA-I proteins and their interactions with lipids in HDL structures. The currently incomplete understanding of the latter issue is largely due to the size heterogeneity of HDLs (diameters range from 7.2 () to 12 nm ()) and the large flexibility of apoA-I. The latter renders the prediction of the positioning of different alpha helices of apoA-I on a spherical surface very difficult. The distribution of lipids inside HDL and their interplay with apoA-I are of profound interest. From a more general perspective, knowledge of the structure of spheroidal HDL is crucial for understanding the conformational changes when HDL makes the transition from discoidal to spheroidal shape, and the trafficking of CHOL and CE through the action of cholesteryl ester transfer protein [43]. Additionally, to design nanoparticles with desired surface and bulk properties, e.g., for controlled transport and release of drugs and contrast agents, it is vital to understand the conformational changes as well as the underlying mechanisms in detail [44]–[51].

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