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Binding Orientations and Lipid Interactions of Human Amylin at Zwitterionic and Anionic Lipid Bilayers.

Qian Z, Jia Y, Wei G - J Diabetes Res (2015)

Bottom Line: The results are compared with those of hIAPP at anionic palmitoyloleoyl-phosphatidylglycerol (POPG) bilayers.Peptide-lipid interaction analyses show that the different binding features of hIAPP at POPC and POPG bilayers are attributed to different magnitudes of electrostatic and hydrogen-bonding interactions with lipids.This study provides mechanistic insights into the different interaction behaviors of hIAPP with zwitterionic and anionic lipid bilayers.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Surface Physics, Key Laboratory for Computational Physical Sciences (Ministry of Education), and Department of Physics, Fudan University, Shanghai 200433, China.

ABSTRACT
Increasing evidence suggests that the interaction of human islet amyloid polypeptide (hIAPP) with lipids may facilitate hIAPP aggregation and cause the death of pancreatic islet β-cells. However, the detailed hIAPP-membrane interactions and the influences of lipid compositions are unclear. In this study, as a first step to understand the mechanism of membrane-mediated hIAPP aggregation, we investigate the binding behaviors of hIAPP monomer at zwitterionic palmitoyloleoyl-phosphatidylcholine (POPC) bilayer by performing atomistic molecular dynamics simulations. The results are compared with those of hIAPP at anionic palmitoyloleoyl-phosphatidylglycerol (POPG) bilayers. We find that the adsorption of hIAPP to POPC bilayer is mainly initiated from the C-terminal region and the peptide adopts a helical structure with multiple binding orientations, while the adsorption to POPG bilayer is mostly initiated from the N-terminal region and hIAPP displays one preferential binding orientation, with its hydrophobic residues exposed to water. hIAPP monomer inserts into POPC lipid bilayers more readily than into POPG bilayers. Peptide-lipid interaction analyses show that the different binding features of hIAPP at POPC and POPG bilayers are attributed to different magnitudes of electrostatic and hydrogen-bonding interactions with lipids. This study provides mechanistic insights into the different interaction behaviors of hIAPP with zwitterionic and anionic lipid bilayers.

No MeSH data available.


Related in: MedlinePlus

The z-positions of the Cα atom (black) and the side chain centroid (red) of each amino acid residue of hIAPP at POPC bilayer surface. For each membrane binding orientation (Fa, Fb, Fc, and Fd), the z-position is averaged using the last 20 ns data of each MD run (see Table 1). The green and blue dashed lines correspond, respectively, to the average position of phosphorus atoms and that of carbon atoms of the ester group of lipids, between which is the headgroup region of the upper leaflet. The residues that have a smaller z-position relative to their adjacent residues in the helical 8–20 region are labeled in the figure.
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fig4: The z-positions of the Cα atom (black) and the side chain centroid (red) of each amino acid residue of hIAPP at POPC bilayer surface. For each membrane binding orientation (Fa, Fb, Fc, and Fd), the z-position is averaged using the last 20 ns data of each MD run (see Table 1). The green and blue dashed lines correspond, respectively, to the average position of phosphorus atoms and that of carbon atoms of the ester group of lipids, between which is the headgroup region of the upper leaflet. The residues that have a smaller z-position relative to their adjacent residues in the helical 8–20 region are labeled in the figure.

Mentions: To investigate the peptide orientation at the membrane-water interface, we plot in Figure 4 the z-positions of Cα-atom and side chain centroid of each residue. As experimental results have shown that the membrane-bound hIAPP monomer adopts an α-helix spanning residues 8~19 [23–25], we classify the membrane binding orientation of hIAPP into four different of orientations (labeled as Fa, Fb, Fc, and Fd) according to z-positions of the residues in the core helix region (residues 8~19). Our recent MD study showed that the side chains of residues R11, F15, and S19 insert more deeply into the anionic POPG bilayer than their neighboring residues [56]. This binding resembles the binding orientation Fd of hIAPP at the zwitterionic POPC bilayer (Figure 4). However, four different membrane binding orientations are observed for hIAPP at zwitterionic POPC bilayers, with almost equal probability. We give in Table 1 the initial states and the final hIAPP orientations in each MD run. As seen from Table 1, hIAPP with the same initial orientation can lead to different final binding orientations, and those with different initial orientations can lead to the same final binding orientation. These results suggest that hIAPP monomer adopts multiple binding orientations at POPC membrane surface independent of its initial orientation.


Binding Orientations and Lipid Interactions of Human Amylin at Zwitterionic and Anionic Lipid Bilayers.

Qian Z, Jia Y, Wei G - J Diabetes Res (2015)

The z-positions of the Cα atom (black) and the side chain centroid (red) of each amino acid residue of hIAPP at POPC bilayer surface. For each membrane binding orientation (Fa, Fb, Fc, and Fd), the z-position is averaged using the last 20 ns data of each MD run (see Table 1). The green and blue dashed lines correspond, respectively, to the average position of phosphorus atoms and that of carbon atoms of the ester group of lipids, between which is the headgroup region of the upper leaflet. The residues that have a smaller z-position relative to their adjacent residues in the helical 8–20 region are labeled in the figure.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4663351&req=5

fig4: The z-positions of the Cα atom (black) and the side chain centroid (red) of each amino acid residue of hIAPP at POPC bilayer surface. For each membrane binding orientation (Fa, Fb, Fc, and Fd), the z-position is averaged using the last 20 ns data of each MD run (see Table 1). The green and blue dashed lines correspond, respectively, to the average position of phosphorus atoms and that of carbon atoms of the ester group of lipids, between which is the headgroup region of the upper leaflet. The residues that have a smaller z-position relative to their adjacent residues in the helical 8–20 region are labeled in the figure.
Mentions: To investigate the peptide orientation at the membrane-water interface, we plot in Figure 4 the z-positions of Cα-atom and side chain centroid of each residue. As experimental results have shown that the membrane-bound hIAPP monomer adopts an α-helix spanning residues 8~19 [23–25], we classify the membrane binding orientation of hIAPP into four different of orientations (labeled as Fa, Fb, Fc, and Fd) according to z-positions of the residues in the core helix region (residues 8~19). Our recent MD study showed that the side chains of residues R11, F15, and S19 insert more deeply into the anionic POPG bilayer than their neighboring residues [56]. This binding resembles the binding orientation Fd of hIAPP at the zwitterionic POPC bilayer (Figure 4). However, four different membrane binding orientations are observed for hIAPP at zwitterionic POPC bilayers, with almost equal probability. We give in Table 1 the initial states and the final hIAPP orientations in each MD run. As seen from Table 1, hIAPP with the same initial orientation can lead to different final binding orientations, and those with different initial orientations can lead to the same final binding orientation. These results suggest that hIAPP monomer adopts multiple binding orientations at POPC membrane surface independent of its initial orientation.

Bottom Line: The results are compared with those of hIAPP at anionic palmitoyloleoyl-phosphatidylglycerol (POPG) bilayers.Peptide-lipid interaction analyses show that the different binding features of hIAPP at POPC and POPG bilayers are attributed to different magnitudes of electrostatic and hydrogen-bonding interactions with lipids.This study provides mechanistic insights into the different interaction behaviors of hIAPP with zwitterionic and anionic lipid bilayers.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Surface Physics, Key Laboratory for Computational Physical Sciences (Ministry of Education), and Department of Physics, Fudan University, Shanghai 200433, China.

ABSTRACT
Increasing evidence suggests that the interaction of human islet amyloid polypeptide (hIAPP) with lipids may facilitate hIAPP aggregation and cause the death of pancreatic islet β-cells. However, the detailed hIAPP-membrane interactions and the influences of lipid compositions are unclear. In this study, as a first step to understand the mechanism of membrane-mediated hIAPP aggregation, we investigate the binding behaviors of hIAPP monomer at zwitterionic palmitoyloleoyl-phosphatidylcholine (POPC) bilayer by performing atomistic molecular dynamics simulations. The results are compared with those of hIAPP at anionic palmitoyloleoyl-phosphatidylglycerol (POPG) bilayers. We find that the adsorption of hIAPP to POPC bilayer is mainly initiated from the C-terminal region and the peptide adopts a helical structure with multiple binding orientations, while the adsorption to POPG bilayer is mostly initiated from the N-terminal region and hIAPP displays one preferential binding orientation, with its hydrophobic residues exposed to water. hIAPP monomer inserts into POPC lipid bilayers more readily than into POPG bilayers. Peptide-lipid interaction analyses show that the different binding features of hIAPP at POPC and POPG bilayers are attributed to different magnitudes of electrostatic and hydrogen-bonding interactions with lipids. This study provides mechanistic insights into the different interaction behaviors of hIAPP with zwitterionic and anionic lipid bilayers.

No MeSH data available.


Related in: MedlinePlus