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Structure and dynamics of amyloid-β segmental polymorphisms.

Berhanu WM, Hansmann UH - PLoS ONE (2012)

Bottom Line: This polymorphism gives rise to differences in morphology, physico-chemical property and level of cellular toxicity.We have investigated the conformational stability of various segmental polymorphisms using molecular dynamics simulations and find that the segmental polymorphic models of Aβ retain a U-shaped architecture.Residues in β-sheet regions have smaller fluctuation while those at the edge and loop region are more mobile.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma, United States of America.

ABSTRACT
It is believed that amyloid-beta (Aβ) aggregates play a role in the pathogenesis of Alzheimer's disease. Aβ molecules form β-sheet structures with multiple interaction sites. This polymorphism gives rise to differences in morphology, physico-chemical property and level of cellular toxicity. We have investigated the conformational stability of various segmental polymorphisms using molecular dynamics simulations and find that the segmental polymorphic models of Aβ retain a U-shaped architecture. Our results demonstrate the importance of inter-sheet side chain-side chain contacts, hydrophobic contacts among the strands (β1 and β2) and of salt bridges in stabilizing the aggregates. Residues in β-sheet regions have smaller fluctuation while those at the edge and loop region are more mobile. The inter-peptide salt bridges between Asp23 and Lys28 are strong compared to intra-chain salt bridge and there is an exchange of the inter-chain salt-bridge with intra-chain salt bridge. As our results suggest that Aβ exists under physiological conditions as an ensemble of distinct segmental polymorphs, it may be necessary to account in the development of therapeutics for Alzheimer's disease the differences in structural stability and aggregation behavior of the various Aβ polymorphic forms.

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Related in: MedlinePlus

Snapshots from MD simulations for double-layered Aβ segmental polymorphism models with the steric zipper interfaces.(A) Aβ16−21P, (B) Aβ16−21AP (C) Aβ27−32, (D) Aβ35−42 and (E) Aβ130−42 interfaces at 0ns, 25ns and 50 ns.
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pone-0041479-g011: Snapshots from MD simulations for double-layered Aβ segmental polymorphism models with the steric zipper interfaces.(A) Aβ16−21P, (B) Aβ16−21AP (C) Aβ27−32, (D) Aβ35−42 and (E) Aβ130−42 interfaces at 0ns, 25ns and 50 ns.

Mentions: Using the dssp tool which determines the existence of hydrogen bonds as criteria for the presence of secondary structure, we analyze the variation of secondary structure during the course of the simulation [65]. The evolution of the secondary structure from two independent trajectories as a function of time is shown in Figure 10 for each system. The models 16–21P and 30–42 which are found to be more stable aggregates have a higher β –sheet contents than the other three systems (Figure 10). Both β-strands of each chain are stable throughout the simulation in all studied systems. However, the peptides located at the ends of the aggregate that occasionally unfold and lose their beta sheet contents. The first two to three amino acid residues in the N terminal and C terminal β-strands adopt a random coil structure throughout the simulations. Snap shots of the segmental polymorphs of Aβ aggregates taken at 0, 25 and 50 ns from two independent trajectories for each of the systems are shown in Figure 11. Visual inspection indicates that the U shaped architecture is retained in most of the system. Residues at N terminal and C terminal and loop region show higher mobility in all models. The inner strands have greater structural stability compared to outer strands that are structurally more flexible (see Figure 11). The outer peptide chains, despite being unstable, do not dissociate from the aggregates. Hence, our analysis of the time evolution of the proposed segmental polymorphs of Aβ indicates that all models are stable and retain the overall U turn structure.


Structure and dynamics of amyloid-β segmental polymorphisms.

Berhanu WM, Hansmann UH - PLoS ONE (2012)

Snapshots from MD simulations for double-layered Aβ segmental polymorphism models with the steric zipper interfaces.(A) Aβ16−21P, (B) Aβ16−21AP (C) Aβ27−32, (D) Aβ35−42 and (E) Aβ130−42 interfaces at 0ns, 25ns and 50 ns.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3404032&req=5

pone-0041479-g011: Snapshots from MD simulations for double-layered Aβ segmental polymorphism models with the steric zipper interfaces.(A) Aβ16−21P, (B) Aβ16−21AP (C) Aβ27−32, (D) Aβ35−42 and (E) Aβ130−42 interfaces at 0ns, 25ns and 50 ns.
Mentions: Using the dssp tool which determines the existence of hydrogen bonds as criteria for the presence of secondary structure, we analyze the variation of secondary structure during the course of the simulation [65]. The evolution of the secondary structure from two independent trajectories as a function of time is shown in Figure 10 for each system. The models 16–21P and 30–42 which are found to be more stable aggregates have a higher β –sheet contents than the other three systems (Figure 10). Both β-strands of each chain are stable throughout the simulation in all studied systems. However, the peptides located at the ends of the aggregate that occasionally unfold and lose their beta sheet contents. The first two to three amino acid residues in the N terminal and C terminal β-strands adopt a random coil structure throughout the simulations. Snap shots of the segmental polymorphs of Aβ aggregates taken at 0, 25 and 50 ns from two independent trajectories for each of the systems are shown in Figure 11. Visual inspection indicates that the U shaped architecture is retained in most of the system. Residues at N terminal and C terminal and loop region show higher mobility in all models. The inner strands have greater structural stability compared to outer strands that are structurally more flexible (see Figure 11). The outer peptide chains, despite being unstable, do not dissociate from the aggregates. Hence, our analysis of the time evolution of the proposed segmental polymorphs of Aβ indicates that all models are stable and retain the overall U turn structure.

Bottom Line: This polymorphism gives rise to differences in morphology, physico-chemical property and level of cellular toxicity.We have investigated the conformational stability of various segmental polymorphisms using molecular dynamics simulations and find that the segmental polymorphic models of Aβ retain a U-shaped architecture.Residues in β-sheet regions have smaller fluctuation while those at the edge and loop region are more mobile.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma, United States of America.

ABSTRACT
It is believed that amyloid-beta (Aβ) aggregates play a role in the pathogenesis of Alzheimer's disease. Aβ molecules form β-sheet structures with multiple interaction sites. This polymorphism gives rise to differences in morphology, physico-chemical property and level of cellular toxicity. We have investigated the conformational stability of various segmental polymorphisms using molecular dynamics simulations and find that the segmental polymorphic models of Aβ retain a U-shaped architecture. Our results demonstrate the importance of inter-sheet side chain-side chain contacts, hydrophobic contacts among the strands (β1 and β2) and of salt bridges in stabilizing the aggregates. Residues in β-sheet regions have smaller fluctuation while those at the edge and loop region are more mobile. The inter-peptide salt bridges between Asp23 and Lys28 are strong compared to intra-chain salt bridge and there is an exchange of the inter-chain salt-bridge with intra-chain salt bridge. As our results suggest that Aβ exists under physiological conditions as an ensemble of distinct segmental polymorphs, it may be necessary to account in the development of therapeutics for Alzheimer's disease the differences in structural stability and aggregation behavior of the various Aβ polymorphic forms.

Show MeSH
Related in: MedlinePlus