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Dynamics of the Glycophorin A Dimer in Membranes of Native-Like Composition Uncovered by Coarse-Grained Molecular Dynamics Simulations.

Flinner N, Schleiff E - PLoS ONE (2015)

Bottom Line: It was documented that molecular dynamics simulations of an idealized plasma membrane model result in formation of membrane areas where either saturated lipids and cholesterol (liquid-ordered character, Lo) or unsaturated lipids (liquid-disordered character, Ld) were enriched.Moreover, it is an important factor for the reproduction of the dynamic behavior of the protein found in its native environment.Therefore, we present structural information on the glycophorin A dimer distribution in the plasma membrane in the absence of other factors like e.g. lipid anchors in a coarse grain resolution.

View Article: PubMed Central - PubMed

Affiliation: Department of Biosciences, Molecular Cell Biology of Plants, Goethe University, Max von Laue Str. 9, 60438, Frankfurt/Main, Germany.

ABSTRACT
Membranes are central for cells as borders to the environment or intracellular organelle definition. They are composed of and harbor different molecules like various lipid species and sterols, and they are generally crowded with proteins. The membrane system is very dynamic and components show lateral, rotational and translational diffusion. The consequence of the latter is that phase separation can occur in membranes in vivo and in vitro. It was documented that molecular dynamics simulations of an idealized plasma membrane model result in formation of membrane areas where either saturated lipids and cholesterol (liquid-ordered character, Lo) or unsaturated lipids (liquid-disordered character, Ld) were enriched. Furthermore, current discussions favor the idea that proteins are sorted into the liquid-disordered phase of model membranes, but experimental support for the behavior of isolated proteins in native membranes is sparse. To gain insight into the protein behavior we built a model of the red blood cell membrane with integrated glycophorin A dimer. The sorting and the dynamics of the dimer were subsequently explored by coarse-grained molecular dynamics simulations. In addition, we inspected the impact of lipid head groups and the presence of cholesterol within the membrane on the dynamics of the dimer within the membrane. We observed that cholesterol is important for the formation of membrane areas with Lo and Ld character. Moreover, it is an important factor for the reproduction of the dynamic behavior of the protein found in its native environment. The protein dimer was exclusively sorted into the domain of Ld character in the model red blood cell plasma membrane. Therefore, we present structural information on the glycophorin A dimer distribution in the plasma membrane in the absence of other factors like e.g. lipid anchors in a coarse grain resolution.

No MeSH data available.


Related in: MedlinePlus

Model of the RBC plasma membrane.(A) The native membrane system in the simulation box after 10 μs simulation is shown. All water molecules are removed for clarity. The protein is shown in stick representation (rose). For lipids only one bead is displayed: For cholesterol (CHOL) the ROH bead (hydroxyl group(grey), for PC (blue), SM (green), PS (red), PE (orange) and PE-pl (yellow) one bead of the lipid linker (GL1 or AM1). The pie chart displays the composition of the native-like membrane. The outer ring corresponds to the head group and the inner ring to the fatty acid. Because cholesterol does not contain a classical fatty acid, only one ring is displayed. (B) Position of the ROH bead of a representative cholesterol molecule during the simulation of the native-like membrane. The dark grey areas indicate the position (average ± 2*standard derivation) of the lipid backbone (bead GL1 of PE 16:0/18:1 for the inner leaflet and bead AM1 of SM for the outer leaflet). (C) Density profile across the native-like membrane for one representative simulation. For all lipids the density of the outermost bead is shown (cholesterol: ROH; PC and SM: NC3; PS: CNO; PE and PE-pl: NH3). The color code is given in A.
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pone.0133999.g001: Model of the RBC plasma membrane.(A) The native membrane system in the simulation box after 10 μs simulation is shown. All water molecules are removed for clarity. The protein is shown in stick representation (rose). For lipids only one bead is displayed: For cholesterol (CHOL) the ROH bead (hydroxyl group(grey), for PC (blue), SM (green), PS (red), PE (orange) and PE-pl (yellow) one bead of the lipid linker (GL1 or AM1). The pie chart displays the composition of the native-like membrane. The outer ring corresponds to the head group and the inner ring to the fatty acid. Because cholesterol does not contain a classical fatty acid, only one ring is displayed. (B) Position of the ROH bead of a representative cholesterol molecule during the simulation of the native-like membrane. The dark grey areas indicate the position (average ± 2*standard derivation) of the lipid backbone (bead GL1 of PE 16:0/18:1 for the inner leaflet and bead AM1 of SM for the outer leaflet). (C) Density profile across the native-like membrane for one representative simulation. For all lipids the density of the outermost bead is shown (cholesterol: ROH; PC and SM: NC3; PS: CNO; PE and PE-pl: NH3). The color code is given in A.

Mentions: We constructed a model of the RBC plasma membrane with an integrated GpA dimer (Fig 1A; Methods) to investigate the dynamics of the system and the components thereof. The model membrane contains cholesterol, PC, SM, PS, PE as well as PE-pl lipids with fatty acids, which are common for the corresponding head group in ratios according to Leidl and coworkers [1]. Minor lipid components (less than 3%), like for example phosphatidylinositol (PI), were not included into the model. The different lipids were asymmetrically distributed across the membrane according to the distribution in the native membrane [3,4]. Here, PE, PE-pl and PS were exclusively positioned in the inner leaflet, SM was incorporated exclusively into the outer leaflet and PC is present in both leaflets, but with a higher frequency in the outer leaflet (Table 1). At the beginning of the simulation cholesterol was evenly distributed across both leaflets. Due to the high frequency of flip-flop movement of cholesterol during the simulation time of 10 μs (Fig 1B), cholesterol is unevenly distributed between both leaflets as indicated by the density profile of the membrane (Fig 1C). On average the outer leaflet contains ~274 and the inner leaflet ~190 cholesterol molecules after equilibration, while the remaining cholesterol molecules are located in the hydrophobic core of the membrane. This imbalance of cholesterol distribution was also observed by Ingolfsson and coworkers [14]. In agreement the cholesterol flip-flop rates have a half-time of <1 s, as determined by experiments [41]. Thus it is possible that the flipping as determined in here using the Martini force field is may be to fast, although it agrees with former simulation studies.


Dynamics of the Glycophorin A Dimer in Membranes of Native-Like Composition Uncovered by Coarse-Grained Molecular Dynamics Simulations.

Flinner N, Schleiff E - PLoS ONE (2015)

Model of the RBC plasma membrane.(A) The native membrane system in the simulation box after 10 μs simulation is shown. All water molecules are removed for clarity. The protein is shown in stick representation (rose). For lipids only one bead is displayed: For cholesterol (CHOL) the ROH bead (hydroxyl group(grey), for PC (blue), SM (green), PS (red), PE (orange) and PE-pl (yellow) one bead of the lipid linker (GL1 or AM1). The pie chart displays the composition of the native-like membrane. The outer ring corresponds to the head group and the inner ring to the fatty acid. Because cholesterol does not contain a classical fatty acid, only one ring is displayed. (B) Position of the ROH bead of a representative cholesterol molecule during the simulation of the native-like membrane. The dark grey areas indicate the position (average ± 2*standard derivation) of the lipid backbone (bead GL1 of PE 16:0/18:1 for the inner leaflet and bead AM1 of SM for the outer leaflet). (C) Density profile across the native-like membrane for one representative simulation. For all lipids the density of the outermost bead is shown (cholesterol: ROH; PC and SM: NC3; PS: CNO; PE and PE-pl: NH3). The color code is given in A.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4519189&req=5

pone.0133999.g001: Model of the RBC plasma membrane.(A) The native membrane system in the simulation box after 10 μs simulation is shown. All water molecules are removed for clarity. The protein is shown in stick representation (rose). For lipids only one bead is displayed: For cholesterol (CHOL) the ROH bead (hydroxyl group(grey), for PC (blue), SM (green), PS (red), PE (orange) and PE-pl (yellow) one bead of the lipid linker (GL1 or AM1). The pie chart displays the composition of the native-like membrane. The outer ring corresponds to the head group and the inner ring to the fatty acid. Because cholesterol does not contain a classical fatty acid, only one ring is displayed. (B) Position of the ROH bead of a representative cholesterol molecule during the simulation of the native-like membrane. The dark grey areas indicate the position (average ± 2*standard derivation) of the lipid backbone (bead GL1 of PE 16:0/18:1 for the inner leaflet and bead AM1 of SM for the outer leaflet). (C) Density profile across the native-like membrane for one representative simulation. For all lipids the density of the outermost bead is shown (cholesterol: ROH; PC and SM: NC3; PS: CNO; PE and PE-pl: NH3). The color code is given in A.
Mentions: We constructed a model of the RBC plasma membrane with an integrated GpA dimer (Fig 1A; Methods) to investigate the dynamics of the system and the components thereof. The model membrane contains cholesterol, PC, SM, PS, PE as well as PE-pl lipids with fatty acids, which are common for the corresponding head group in ratios according to Leidl and coworkers [1]. Minor lipid components (less than 3%), like for example phosphatidylinositol (PI), were not included into the model. The different lipids were asymmetrically distributed across the membrane according to the distribution in the native membrane [3,4]. Here, PE, PE-pl and PS were exclusively positioned in the inner leaflet, SM was incorporated exclusively into the outer leaflet and PC is present in both leaflets, but with a higher frequency in the outer leaflet (Table 1). At the beginning of the simulation cholesterol was evenly distributed across both leaflets. Due to the high frequency of flip-flop movement of cholesterol during the simulation time of 10 μs (Fig 1B), cholesterol is unevenly distributed between both leaflets as indicated by the density profile of the membrane (Fig 1C). On average the outer leaflet contains ~274 and the inner leaflet ~190 cholesterol molecules after equilibration, while the remaining cholesterol molecules are located in the hydrophobic core of the membrane. This imbalance of cholesterol distribution was also observed by Ingolfsson and coworkers [14]. In agreement the cholesterol flip-flop rates have a half-time of <1 s, as determined by experiments [41]. Thus it is possible that the flipping as determined in here using the Martini force field is may be to fast, although it agrees with former simulation studies.

Bottom Line: It was documented that molecular dynamics simulations of an idealized plasma membrane model result in formation of membrane areas where either saturated lipids and cholesterol (liquid-ordered character, Lo) or unsaturated lipids (liquid-disordered character, Ld) were enriched.Moreover, it is an important factor for the reproduction of the dynamic behavior of the protein found in its native environment.Therefore, we present structural information on the glycophorin A dimer distribution in the plasma membrane in the absence of other factors like e.g. lipid anchors in a coarse grain resolution.

View Article: PubMed Central - PubMed

Affiliation: Department of Biosciences, Molecular Cell Biology of Plants, Goethe University, Max von Laue Str. 9, 60438, Frankfurt/Main, Germany.

ABSTRACT
Membranes are central for cells as borders to the environment or intracellular organelle definition. They are composed of and harbor different molecules like various lipid species and sterols, and they are generally crowded with proteins. The membrane system is very dynamic and components show lateral, rotational and translational diffusion. The consequence of the latter is that phase separation can occur in membranes in vivo and in vitro. It was documented that molecular dynamics simulations of an idealized plasma membrane model result in formation of membrane areas where either saturated lipids and cholesterol (liquid-ordered character, Lo) or unsaturated lipids (liquid-disordered character, Ld) were enriched. Furthermore, current discussions favor the idea that proteins are sorted into the liquid-disordered phase of model membranes, but experimental support for the behavior of isolated proteins in native membranes is sparse. To gain insight into the protein behavior we built a model of the red blood cell membrane with integrated glycophorin A dimer. The sorting and the dynamics of the dimer were subsequently explored by coarse-grained molecular dynamics simulations. In addition, we inspected the impact of lipid head groups and the presence of cholesterol within the membrane on the dynamics of the dimer within the membrane. We observed that cholesterol is important for the formation of membrane areas with Lo and Ld character. Moreover, it is an important factor for the reproduction of the dynamic behavior of the protein found in its native environment. The protein dimer was exclusively sorted into the domain of Ld character in the model red blood cell plasma membrane. Therefore, we present structural information on the glycophorin A dimer distribution in the plasma membrane in the absence of other factors like e.g. lipid anchors in a coarse grain resolution.

No MeSH data available.


Related in: MedlinePlus