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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

Influence of membrane-bound hIAPP monomer on the tail ordering of POPC lipids. (a) Lipid tail order parameter SCD of acyl chain 1 (sn-1). In the calculation, the lipids within 1 nm (minimum distance) from any nonhydrogen atom of hIAPP peptide are considered. We also give the SCD of a neat POPC lipid bilayer for comparison, obtained from the last 10 ns of a 100 ns MD run. (b) Local membrane thickness for lipids within six different cutoffs from hIAPP peptide. The thickness is calculated using the average z-position of the phosphorus atoms in the upper leaflet and that in the lower leaflet. The upper and lower bounds of the thickness of a neat POPC bilayer membrane (36.7 ± 0.5 Å) are plotted in blue dashed lines, consistent with that in [69].
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fig8: Influence of membrane-bound hIAPP monomer on the tail ordering of POPC lipids. (a) Lipid tail order parameter SCD of acyl chain 1 (sn-1). In the calculation, the lipids within 1 nm (minimum distance) from any nonhydrogen atom of hIAPP peptide are considered. We also give the SCD of a neat POPC lipid bilayer for comparison, obtained from the last 10 ns of a 100 ns MD run. (b) Local membrane thickness for lipids within six different cutoffs from hIAPP peptide. The thickness is calculated using the average z-position of the phosphorus atoms in the upper leaflet and that in the lower leaflet. The upper and lower bounds of the thickness of a neat POPC bilayer membrane (36.7 ± 0.5 Å) are plotted in blue dashed lines, consistent with that in [69].

Mentions: The toxicity of hIAPP and membrane disruption are suggested to be associated with hIAPP-membrane interactions [29, 95]. To examine the effect of membrane-bound hIAPP monomer on the POPC membrane, we calculate the lipid tail order parameter SCD of acyl chain 1 (sn-1) and the local membrane thickness (see Figure 8). The SCD value is calculated by the formula SCD = 0.5〈3cos2⁡θ − 1〉, where θ represents the angle of the C–H bond vector (in the simulation) or the C–D bond vector (in the experiment) with the bilayer normal. The angular brackets indicate averaging over lipids and over time [97]. As seen from Figure 8, the averaged SCD value is within the error bar of the neat POPC lipid bilayer, implying that lipid interaction of hIAPP monomer does not disturb the membrane integrity. The calculated local thickness of lipid bilayers in Figure 8(b) using different cutoff demonstrates that hIAPP-lipid interaction influences the local thickness of POPC bilayer. The influence can be neglected when the cutoff is larger than 3 nm. These results suggest that the binding of hIAPP monomer at the POPC membrane surface has negligible disturbance on the integrity of the POPC bilayer, which provides atomic-level evidence that membrane-bound hIAPP monomer does not cause membrane disruption [29, 95]. However, it is expected that when the concentration of membrane-bound peptide reaches a critical value, the hIAPP-lipid interaction may cause membrane disruption.


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

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

Influence of membrane-bound hIAPP monomer on the tail ordering of POPC lipids. (a) Lipid tail order parameter SCD of acyl chain 1 (sn-1). In the calculation, the lipids within 1 nm (minimum distance) from any nonhydrogen atom of hIAPP peptide are considered. We also give the SCD of a neat POPC lipid bilayer for comparison, obtained from the last 10 ns of a 100 ns MD run. (b) Local membrane thickness for lipids within six different cutoffs from hIAPP peptide. The thickness is calculated using the average z-position of the phosphorus atoms in the upper leaflet and that in the lower leaflet. The upper and lower bounds of the thickness of a neat POPC bilayer membrane (36.7 ± 0.5 Å) are plotted in blue dashed lines, consistent with that in [69].
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4663351&req=5

fig8: Influence of membrane-bound hIAPP monomer on the tail ordering of POPC lipids. (a) Lipid tail order parameter SCD of acyl chain 1 (sn-1). In the calculation, the lipids within 1 nm (minimum distance) from any nonhydrogen atom of hIAPP peptide are considered. We also give the SCD of a neat POPC lipid bilayer for comparison, obtained from the last 10 ns of a 100 ns MD run. (b) Local membrane thickness for lipids within six different cutoffs from hIAPP peptide. The thickness is calculated using the average z-position of the phosphorus atoms in the upper leaflet and that in the lower leaflet. The upper and lower bounds of the thickness of a neat POPC bilayer membrane (36.7 ± 0.5 Å) are plotted in blue dashed lines, consistent with that in [69].
Mentions: The toxicity of hIAPP and membrane disruption are suggested to be associated with hIAPP-membrane interactions [29, 95]. To examine the effect of membrane-bound hIAPP monomer on the POPC membrane, we calculate the lipid tail order parameter SCD of acyl chain 1 (sn-1) and the local membrane thickness (see Figure 8). The SCD value is calculated by the formula SCD = 0.5〈3cos2⁡θ − 1〉, where θ represents the angle of the C–H bond vector (in the simulation) or the C–D bond vector (in the experiment) with the bilayer normal. The angular brackets indicate averaging over lipids and over time [97]. As seen from Figure 8, the averaged SCD value is within the error bar of the neat POPC lipid bilayer, implying that lipid interaction of hIAPP monomer does not disturb the membrane integrity. The calculated local thickness of lipid bilayers in Figure 8(b) using different cutoff demonstrates that hIAPP-lipid interaction influences the local thickness of POPC bilayer. The influence can be neglected when the cutoff is larger than 3 nm. These results suggest that the binding of hIAPP monomer at the POPC membrane surface has negligible disturbance on the integrity of the POPC bilayer, which provides atomic-level evidence that membrane-bound hIAPP monomer does not cause membrane disruption [29, 95]. However, it is expected that when the concentration of membrane-bound peptide reaches a critical value, the hIAPP-lipid interaction may cause membrane disruption.

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