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Amyloidogenesis abolished by proline substitutions but enhanced by lipid binding.

Jiang P, Xu W, Mu Y - PLoS Comput. Biol. (2009)

Bottom Line: The hydrophobic interaction between lipid tails and residues at positions 23-25 is found to stabilize the ordered beta-sheet structure, indicating a catalysis role of lipid molecules in hIAPP20-29 self-assembly.The rat IAPP variants with three proline residues maintain unstructured micelle-like oligomers, which is consistent with non-amyloidogenic behavior observed in experimental studies.Our study provides the atomic resolution descriptions of the catalytic function of lipid molecules on the aggregation of IAPP peptides.

View Article: PubMed Central - PubMed

Affiliation: School of Biological Sciences, Nanyang Technological University, Singapore.

ABSTRACT
The influence of lipid molecules on the aggregation of a highly amyloidogenic segment of human islet amyloid polypeptide, hIAPP20-29, and the corresponding sequence from rat has been studied by all-atom replica exchange molecular dynamics (REMD) simulations with explicit solvent model. hIAPP20-29 fragments aggregate into partially ordered beta-sheet oligomers and then undergo large conformational reorganization and convert into parallel/antiparallel beta-sheet oligomers in mixed in-register and out-of-register patterns. The hydrophobic interaction between lipid tails and residues at positions 23-25 is found to stabilize the ordered beta-sheet structure, indicating a catalysis role of lipid molecules in hIAPP20-29 self-assembly. The rat IAPP variants with three proline residues maintain unstructured micelle-like oligomers, which is consistent with non-amyloidogenic behavior observed in experimental studies. Our study provides the atomic resolution descriptions of the catalytic function of lipid molecules on the aggregation of IAPP peptides.

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The influence of lipid on peptide aggregation.(A). Occurrences of atomic contacts (NC) between heavy atoms on lipid head (square symbol, sold line) or tail (circle symbol, dashed line) groups and Cα atoms on hIAPP fragment. Distance cutoff is 0.6 nm. The counts are scaled by the total atom number of head or tail group in order to prevent the bias favored by large atom number of tail group. (B). Temperature dependence of number of β-bridges NB averaged over the ensemble trajectories at the same temperature.
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pcbi-1000357-g009: The influence of lipid on peptide aggregation.(A). Occurrences of atomic contacts (NC) between heavy atoms on lipid head (square symbol, sold line) or tail (circle symbol, dashed line) groups and Cα atoms on hIAPP fragment. Distance cutoff is 0.6 nm. The counts are scaled by the total atom number of head or tail group in order to prevent the bias favored by large atom number of tail group. (B). Temperature dependence of number of β-bridges NB averaged over the ensemble trajectories at the same temperature.

Mentions: The lipid-associated peptide toxicity and aggregation enhancement has been widely established under a variety of lipid models such as micellar [62] and bilayer membranes [25], even free fatty acids and lipids [63],[64]. The mature amyloid fibrils are found to contain a portion of lipids which are supposed to be taken up from membranes and wrapped together with peptide while aggregation goes on [25]. Based on results discussed previously, the presence of a lipid molecule has clear effects on the aggregation process of hIAPP peptides: The propensities for β-sheet structure of residues 20–23 in hIAPP/lipid system are increased and their propensities for turns and bends are correspondingly reduced (Figure 5); the value of NB needed for the formation of β-sheet oligomers is consistently reduced by one in the presence of the lipid molecule (Figure 7). To probe the lipid-peptide binding manners in a statistical way, the occurrences of atomic contacts (NC) between heavy atoms on lipid head/tail groups and Cα atoms on hIAPP fragment are calculated (Figure 9A). All residues have similar probabilities of contacting with head group. The general pattern of such contact is the H-bonds formed between head group and polar side chains. In contrast, the probabilities of contacting the tail group for different residues are quite distinct. Nonpolar residues show obviously higher inclination, especially for residues F23, G24, and A25, indicating a specific lipid-binding site. The binding site is exactly the region which has high SSP for turns and bends in the absence of lipid (Figure 5). The increased propensity for β-sheet of this region in hIAPP/lipid (Figure 5C) is due to the specific binding of nonpolar lipid tails.


Amyloidogenesis abolished by proline substitutions but enhanced by lipid binding.

Jiang P, Xu W, Mu Y - PLoS Comput. Biol. (2009)

The influence of lipid on peptide aggregation.(A). Occurrences of atomic contacts (NC) between heavy atoms on lipid head (square symbol, sold line) or tail (circle symbol, dashed line) groups and Cα atoms on hIAPP fragment. Distance cutoff is 0.6 nm. The counts are scaled by the total atom number of head or tail group in order to prevent the bias favored by large atom number of tail group. (B). Temperature dependence of number of β-bridges NB averaged over the ensemble trajectories at the same temperature.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2663790&req=5

pcbi-1000357-g009: The influence of lipid on peptide aggregation.(A). Occurrences of atomic contacts (NC) between heavy atoms on lipid head (square symbol, sold line) or tail (circle symbol, dashed line) groups and Cα atoms on hIAPP fragment. Distance cutoff is 0.6 nm. The counts are scaled by the total atom number of head or tail group in order to prevent the bias favored by large atom number of tail group. (B). Temperature dependence of number of β-bridges NB averaged over the ensemble trajectories at the same temperature.
Mentions: The lipid-associated peptide toxicity and aggregation enhancement has been widely established under a variety of lipid models such as micellar [62] and bilayer membranes [25], even free fatty acids and lipids [63],[64]. The mature amyloid fibrils are found to contain a portion of lipids which are supposed to be taken up from membranes and wrapped together with peptide while aggregation goes on [25]. Based on results discussed previously, the presence of a lipid molecule has clear effects on the aggregation process of hIAPP peptides: The propensities for β-sheet structure of residues 20–23 in hIAPP/lipid system are increased and their propensities for turns and bends are correspondingly reduced (Figure 5); the value of NB needed for the formation of β-sheet oligomers is consistently reduced by one in the presence of the lipid molecule (Figure 7). To probe the lipid-peptide binding manners in a statistical way, the occurrences of atomic contacts (NC) between heavy atoms on lipid head/tail groups and Cα atoms on hIAPP fragment are calculated (Figure 9A). All residues have similar probabilities of contacting with head group. The general pattern of such contact is the H-bonds formed between head group and polar side chains. In contrast, the probabilities of contacting the tail group for different residues are quite distinct. Nonpolar residues show obviously higher inclination, especially for residues F23, G24, and A25, indicating a specific lipid-binding site. The binding site is exactly the region which has high SSP for turns and bends in the absence of lipid (Figure 5). The increased propensity for β-sheet of this region in hIAPP/lipid (Figure 5C) is due to the specific binding of nonpolar lipid tails.

Bottom Line: The hydrophobic interaction between lipid tails and residues at positions 23-25 is found to stabilize the ordered beta-sheet structure, indicating a catalysis role of lipid molecules in hIAPP20-29 self-assembly.The rat IAPP variants with three proline residues maintain unstructured micelle-like oligomers, which is consistent with non-amyloidogenic behavior observed in experimental studies.Our study provides the atomic resolution descriptions of the catalytic function of lipid molecules on the aggregation of IAPP peptides.

View Article: PubMed Central - PubMed

Affiliation: School of Biological Sciences, Nanyang Technological University, Singapore.

ABSTRACT
The influence of lipid molecules on the aggregation of a highly amyloidogenic segment of human islet amyloid polypeptide, hIAPP20-29, and the corresponding sequence from rat has been studied by all-atom replica exchange molecular dynamics (REMD) simulations with explicit solvent model. hIAPP20-29 fragments aggregate into partially ordered beta-sheet oligomers and then undergo large conformational reorganization and convert into parallel/antiparallel beta-sheet oligomers in mixed in-register and out-of-register patterns. The hydrophobic interaction between lipid tails and residues at positions 23-25 is found to stabilize the ordered beta-sheet structure, indicating a catalysis role of lipid molecules in hIAPP20-29 self-assembly. The rat IAPP variants with three proline residues maintain unstructured micelle-like oligomers, which is consistent with non-amyloidogenic behavior observed in experimental studies. Our study provides the atomic resolution descriptions of the catalytic function of lipid molecules on the aggregation of IAPP peptides.

Show MeSH
Related in: MedlinePlus