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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

Dynamics of the protein in the RBC plasma membrane.(A) For all ten simulations of the model of the RBC plasma membrane (native-like) the presences of the NMR interface is plotted for each time point in grey. (B) Shown is the frequency of frequent interface clusters (frequency over 10% in all simulations) from all ten simulations per membrane (nFA (red), nFA+CHOL (green), nFA+head (blue), native-like (yellow)). The number of simulations, in which the corresponding interface was identified, is given on the bottom of each cluster (in grey scale). (C) Screenshot of representative structures from cluster 86 (left) and cluster 40 (right) and in the middle a structural alignment is shown. In the screenshot left and right the main interface residues are highlighted in red and in the structural alignment (cluster 86…dark grey, cluster 40…grey) the residues of the GxxxGxxxT motif are highlighted for orientation. Additionally the distances between the glycine and threonine backbone atoms of the GxxxGxxxT interface is given for the structure of cluster 86. (D) The survival time (x-axis) of the NMR interface once it appeared in the simulation (either at the start or by reformation during simulation) is plotted against the probability of the presence of the NMR interface for all four membrane systems.
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pone.0133999.g002: Dynamics of the protein in the RBC plasma membrane.(A) For all ten simulations of the model of the RBC plasma membrane (native-like) the presences of the NMR interface is plotted for each time point in grey. (B) Shown is the frequency of frequent interface clusters (frequency over 10% in all simulations) from all ten simulations per membrane (nFA (red), nFA+CHOL (green), nFA+head (blue), native-like (yellow)). The number of simulations, in which the corresponding interface was identified, is given on the bottom of each cluster (in grey scale). (C) Screenshot of representative structures from cluster 86 (left) and cluster 40 (right) and in the middle a structural alignment is shown. In the screenshot left and right the main interface residues are highlighted in red and in the structural alignment (cluster 86…dark grey, cluster 40…grey) the residues of the GxxxGxxxT motif are highlighted for orientation. Additionally the distances between the glycine and threonine backbone atoms of the GxxxGxxxT interface is given for the structure of cluster 86. (D) The survival time (x-axis) of the NMR interface once it appeared in the simulation (either at the start or by reformation during simulation) is plotted against the probability of the presence of the NMR interface for all four membrane systems.

Mentions: After establishing the model of the RBC membrane we investigated the dynamics of the protein. Initially we analyzed the stability of the NMR interface during the whole simulation time of 10 μs in the model of the RBC membrane and determined which rearrangements could be observed. We performed ten simulations of the whole system with different random seeds. Indeed, in all of the ten simulations a rearrangement of the NMR interface is observed (Fig 2A) and additional interfaces occur. The identification of different interfaces for GpA is not unexpected and was also observed by other approaches: a large dimer interface space for GpA was observed by a surface-based modeling approach [43] and several interfaces were predicted by Monte Carlo simulations to exist in a membrane mimicking environment [44].


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)

Dynamics of the protein in the RBC plasma membrane.(A) For all ten simulations of the model of the RBC plasma membrane (native-like) the presences of the NMR interface is plotted for each time point in grey. (B) Shown is the frequency of frequent interface clusters (frequency over 10% in all simulations) from all ten simulations per membrane (nFA (red), nFA+CHOL (green), nFA+head (blue), native-like (yellow)). The number of simulations, in which the corresponding interface was identified, is given on the bottom of each cluster (in grey scale). (C) Screenshot of representative structures from cluster 86 (left) and cluster 40 (right) and in the middle a structural alignment is shown. In the screenshot left and right the main interface residues are highlighted in red and in the structural alignment (cluster 86…dark grey, cluster 40…grey) the residues of the GxxxGxxxT motif are highlighted for orientation. Additionally the distances between the glycine and threonine backbone atoms of the GxxxGxxxT interface is given for the structure of cluster 86. (D) The survival time (x-axis) of the NMR interface once it appeared in the simulation (either at the start or by reformation during simulation) is plotted against the probability of the presence of the NMR interface for all four membrane systems.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0133999.g002: Dynamics of the protein in the RBC plasma membrane.(A) For all ten simulations of the model of the RBC plasma membrane (native-like) the presences of the NMR interface is plotted for each time point in grey. (B) Shown is the frequency of frequent interface clusters (frequency over 10% in all simulations) from all ten simulations per membrane (nFA (red), nFA+CHOL (green), nFA+head (blue), native-like (yellow)). The number of simulations, in which the corresponding interface was identified, is given on the bottom of each cluster (in grey scale). (C) Screenshot of representative structures from cluster 86 (left) and cluster 40 (right) and in the middle a structural alignment is shown. In the screenshot left and right the main interface residues are highlighted in red and in the structural alignment (cluster 86…dark grey, cluster 40…grey) the residues of the GxxxGxxxT motif are highlighted for orientation. Additionally the distances between the glycine and threonine backbone atoms of the GxxxGxxxT interface is given for the structure of cluster 86. (D) The survival time (x-axis) of the NMR interface once it appeared in the simulation (either at the start or by reformation during simulation) is plotted against the probability of the presence of the NMR interface for all four membrane systems.
Mentions: After establishing the model of the RBC membrane we investigated the dynamics of the protein. Initially we analyzed the stability of the NMR interface during the whole simulation time of 10 μs in the model of the RBC membrane and determined which rearrangements could be observed. We performed ten simulations of the whole system with different random seeds. Indeed, in all of the ten simulations a rearrangement of the NMR interface is observed (Fig 2A) and additional interfaces occur. The identification of different interfaces for GpA is not unexpected and was also observed by other approaches: a large dimer interface space for GpA was observed by a surface-based modeling approach [43] and several interfaces were predicted by Monte Carlo simulations to exist in a membrane mimicking environment [44].

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