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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.

Show MeSH
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 [13].
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pcbi-1000964-g009: 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 [13].

Mentions: The lipid-protein interactions of different moieties of each lipid component showed that POPC, PPC and TG molecules interact with apoA-I residues preferentially through the acyl chains (POPC and PPC glycerol backbone has also a high number of contacts with apoA-I), while CHOL and CE molecules interact with the protein mainly through the sterol ring (see Table S1). To better understand the nature of the interaction between CHOL and apoA-I we also measured the number of lipid-protein contacts per residue (hydrophobic and hydrophilic), shown in Figure 9. It is clear that there is a preferential interaction of CHOL molecules with apoA-I hydrophobic residues, in particular tryptophane (Trp) and phenylalanine (Phe) having aromatic side chains, but also valine (Val) and leucine (Leu). Highly preferred interaction with Trp and Phe is understandable through findings of aromatic ring pairing in e.g. known protein structures [62]. We also observe a relevant number of contacts with apoA-I hydrophilic residues with aromatic side chains such as tyrosine (Tyr) and histidine (His). This is not surprising, as Tyr has a hydrophobicity comparable to Phe as has been shown experimentally by Wimley and White [63] through the determination of a hydrophobicity scale for proteins at membrane interfaces. There are less contacts of CHOL molecules with the other apoA-I hydrophilic residues, namely serine (Ser), threonine (Thr) and asparagine (Asp) being the most attractive ones. These results are in good agreement with the observed large number of contacts of the sterol ring of CHOL molecules with protein residues.


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)

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 [13].
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1000964-g009: 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 [13].
Mentions: The lipid-protein interactions of different moieties of each lipid component showed that POPC, PPC and TG molecules interact with apoA-I residues preferentially through the acyl chains (POPC and PPC glycerol backbone has also a high number of contacts with apoA-I), while CHOL and CE molecules interact with the protein mainly through the sterol ring (see Table S1). To better understand the nature of the interaction between CHOL and apoA-I we also measured the number of lipid-protein contacts per residue (hydrophobic and hydrophilic), shown in Figure 9. It is clear that there is a preferential interaction of CHOL molecules with apoA-I hydrophobic residues, in particular tryptophane (Trp) and phenylalanine (Phe) having aromatic side chains, but also valine (Val) and leucine (Leu). Highly preferred interaction with Trp and Phe is understandable through findings of aromatic ring pairing in e.g. known protein structures [62]. We also observe a relevant number of contacts with apoA-I hydrophilic residues with aromatic side chains such as tyrosine (Tyr) and histidine (His). This is not surprising, as Tyr has a hydrophobicity comparable to Phe as has been shown experimentally by Wimley and White [63] through the determination of a hydrophobicity scale for proteins at membrane interfaces. There are less contacts of CHOL molecules with the other apoA-I hydrophilic residues, namely serine (Ser), threonine (Thr) and asparagine (Asp) being the most attractive ones. These results are in good agreement with the observed large number of contacts of the sterol ring of CHOL molecules with protein residues.

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