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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

Detailed analysis of a representative MD trajectory of hIAPP adsorption to POPC bilayer surface, starting from the initial state S(0). (a) Snapshots at t = 0, 12, 40, and 120 ns. Each snapshot is displayed using the same representations as those used in Figure 1. (b) Time evolution of the number of contacts and the number of H-bonds between hIAPP peptide and the POPC lipid bilayer. (c) Time evolution of z-position and interaction energy between lipid bilayer and the negatively charged residues K1 (black) and R11 (red). The solid and dashed lines correspond to z-position and interaction energy, respectively. We only present the data of first 50 ns in order to show the initial adsorption process clearly.
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fig3: Detailed analysis of a representative MD trajectory of hIAPP adsorption to POPC bilayer surface, starting from the initial state S(0). (a) Snapshots at t = 0, 12, 40, and 120 ns. Each snapshot is displayed using the same representations as those used in Figure 1. (b) Time evolution of the number of contacts and the number of H-bonds between hIAPP peptide and the POPC lipid bilayer. (c) Time evolution of z-position and interaction energy between lipid bilayer and the negatively charged residues K1 (black) and R11 (red). The solid and dashed lines correspond to z-position and interaction energy, respectively. We only present the data of first 50 ns in order to show the initial adsorption process clearly.

Mentions: To give the detailed adsorption process, we show in Figure 3 the snapshots at different time points and the time evolution of the contact number and hydrogen bond number between residue 1~19/20~37 and POPC headgroups in a representative MD run started from the initial state S(0). It can be seen from Figure 3 that in the initial state, the hIAPP monomer is placed in water parallel to the POPC bilayer with the side chain of residue K1 pointing toward membrane surface. The contact numbers between the C-terminal residues 20~37 and POPC lipids increase with simulation time. At t = 12 ns, the C-terminal residues 20~37 adsorb to the membrane surface prior to the N-terminal residues. Then, it takes tens of nanoseconds for residues 20~37 to adjust their side chains. At t = 50 ns, hIAPP monomer is mostly adsorbed to membrane surface and stays on the bilayer surface in the remaining 70 ns of MD simulation. The larger contact number of C-terminal residues 20~37 with POPC lipids with respect to the N-terminal residues 1~19 indicates that the C-terminal residues 20~37 interact with the membrane more strongly than the N-terminal residues 1~19. As seen from Figure 3(b), the adsorption process is accompanied by the formation of H-bonds between hIAPP and the headgroups of POPC lipids. Figure 3(c) gives the time evolution of the z-position of the positively charged residues (K1 and R11) and their interaction energy with POPC bilayer within the first 50 ns of MD simulation. It is observed that K1 and R11 approach to the membrane surface at ~50 ns (solid line in Figure 3(c)), while the C-terminal residues reach to the bilayer surface within 15 ns (see Figure 2). In addition, the interaction energy between the POPC bilayer and residue K1/R11 is positive during the first 40/30 ns of simulation, reflecting the existence of repulsive interaction between the positively charged residues and the POPC lipids in the beginning of the simulations. It is known that a POPC lipid molecule is composed of a positively charged choline, a negatively charged phosphate group and hydrophobic fatty acids. Although the POPC lipid has no net charge, the positively charged choline is located closer to the membrane-water interface than the negatively charged phosphate group (see Section 3.3 for more details about the location of choline and phosphate groups), which leads to net repulsive interactions during the adsorption process. This net repulsive interaction disfavors the N-terminal residues to adsorb first to the membrane surface, which explains the observed C-terminal-initiated adsorption behavior (see Figure 2). These results provide the first step of hIAPP-membrane interactions. Interestingly, both insertion and some helical folding were observed in our recent REMD study on hIAPP(1–19) peptide [64]. Based on the results of our REMD study [64], we deduce that the next step of hIAPP-bilayer interaction might proceeds through insertion of partially ordered structures followed by helical folding within the interface [90, 91]. However, the exact mechanism remains clearly to be determined.


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

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

Detailed analysis of a representative MD trajectory of hIAPP adsorption to POPC bilayer surface, starting from the initial state S(0). (a) Snapshots at t = 0, 12, 40, and 120 ns. Each snapshot is displayed using the same representations as those used in Figure 1. (b) Time evolution of the number of contacts and the number of H-bonds between hIAPP peptide and the POPC lipid bilayer. (c) Time evolution of z-position and interaction energy between lipid bilayer and the negatively charged residues K1 (black) and R11 (red). The solid and dashed lines correspond to z-position and interaction energy, respectively. We only present the data of first 50 ns in order to show the initial adsorption process clearly.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4663351&req=5

fig3: Detailed analysis of a representative MD trajectory of hIAPP adsorption to POPC bilayer surface, starting from the initial state S(0). (a) Snapshots at t = 0, 12, 40, and 120 ns. Each snapshot is displayed using the same representations as those used in Figure 1. (b) Time evolution of the number of contacts and the number of H-bonds between hIAPP peptide and the POPC lipid bilayer. (c) Time evolution of z-position and interaction energy between lipid bilayer and the negatively charged residues K1 (black) and R11 (red). The solid and dashed lines correspond to z-position and interaction energy, respectively. We only present the data of first 50 ns in order to show the initial adsorption process clearly.
Mentions: To give the detailed adsorption process, we show in Figure 3 the snapshots at different time points and the time evolution of the contact number and hydrogen bond number between residue 1~19/20~37 and POPC headgroups in a representative MD run started from the initial state S(0). It can be seen from Figure 3 that in the initial state, the hIAPP monomer is placed in water parallel to the POPC bilayer with the side chain of residue K1 pointing toward membrane surface. The contact numbers between the C-terminal residues 20~37 and POPC lipids increase with simulation time. At t = 12 ns, the C-terminal residues 20~37 adsorb to the membrane surface prior to the N-terminal residues. Then, it takes tens of nanoseconds for residues 20~37 to adjust their side chains. At t = 50 ns, hIAPP monomer is mostly adsorbed to membrane surface and stays on the bilayer surface in the remaining 70 ns of MD simulation. The larger contact number of C-terminal residues 20~37 with POPC lipids with respect to the N-terminal residues 1~19 indicates that the C-terminal residues 20~37 interact with the membrane more strongly than the N-terminal residues 1~19. As seen from Figure 3(b), the adsorption process is accompanied by the formation of H-bonds between hIAPP and the headgroups of POPC lipids. Figure 3(c) gives the time evolution of the z-position of the positively charged residues (K1 and R11) and their interaction energy with POPC bilayer within the first 50 ns of MD simulation. It is observed that K1 and R11 approach to the membrane surface at ~50 ns (solid line in Figure 3(c)), while the C-terminal residues reach to the bilayer surface within 15 ns (see Figure 2). In addition, the interaction energy between the POPC bilayer and residue K1/R11 is positive during the first 40/30 ns of simulation, reflecting the existence of repulsive interaction between the positively charged residues and the POPC lipids in the beginning of the simulations. It is known that a POPC lipid molecule is composed of a positively charged choline, a negatively charged phosphate group and hydrophobic fatty acids. Although the POPC lipid has no net charge, the positively charged choline is located closer to the membrane-water interface than the negatively charged phosphate group (see Section 3.3 for more details about the location of choline and phosphate groups), which leads to net repulsive interactions during the adsorption process. This net repulsive interaction disfavors the N-terminal residues to adsorb first to the membrane surface, which explains the observed C-terminal-initiated adsorption behavior (see Figure 2). These results provide the first step of hIAPP-membrane interactions. Interestingly, both insertion and some helical folding were observed in our recent REMD study on hIAPP(1–19) peptide [64]. Based on the results of our REMD study [64], we deduce that the next step of hIAPP-bilayer interaction might proceeds through insertion of partially ordered structures followed by helical folding within the interface [90, 91]. However, the exact mechanism remains clearly to be determined.

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