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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

Comparison of all-atom root-mean-square deviation and solvent accessible surface areas of Aβ segmental polymorphism models.Backbone Cα atom-positional root-mean-square fluctuations, RMSF, along the amino acid sequence for the five models (A). The results are the average of two independent salutation of each system. The variation of average per residue solvent accessible surface area for each models (B). Red, 16–21P; pink, 16–21AP; blue, 27–32; green, 35–42; yellow, 30–42.
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pone-0041479-g003: Comparison of all-atom root-mean-square deviation and solvent accessible surface areas of Aβ segmental polymorphism models.Backbone Cα atom-positional root-mean-square fluctuations, RMSF, along the amino acid sequence for the five models (A). The results are the average of two independent salutation of each system. The variation of average per residue solvent accessible surface area for each models (B). Red, 16–21P; pink, 16–21AP; blue, 27–32; green, 35–42; yellow, 30–42.

Mentions: We assess the local dynamics and flexibility of the each part of the five segmental polymorphic models of Aβ by calculating the residue-based root mean square fluctuations (RMSF) of the corresponding backbones with respect to their energy minimized structure. Residues in the turn region exhibited a higher flexibility than those in the β-strand regions, except for residues near the N/C-termini (Figure 3A). By visual inspection of the trajectories we find that all 10-mer structures maintain the U turn or “β arch” motif without disassociation of the β-strands. The model based on the 16–21 parallel steric zippers with an NN interface is more stable than the antiparallel counter parts (Figure 3A). This is in agreement with the RMSD result above and with the recent ssNMR experimental study of the Iowa mutant of amyloid β [57]. The model covering 30–40 with longer interface is the most stable polymorph, with smaller fluctuation in both β1 and β2. The terminal amino acids of all structures undergo more dynamic reorientation and are more disordered due to exposure to the solvent molecules (Figure 3A).


Structure and dynamics of amyloid-β segmental polymorphisms.

Berhanu WM, Hansmann UH - PLoS ONE (2012)

Comparison of all-atom root-mean-square deviation and solvent accessible surface areas of Aβ segmental polymorphism models.Backbone Cα atom-positional root-mean-square fluctuations, RMSF, along the amino acid sequence for the five models (A). The results are the average of two independent salutation of each system. The variation of average per residue solvent accessible surface area for each models (B). Red, 16–21P; pink, 16–21AP; blue, 27–32; green, 35–42; yellow, 30–42.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0041479-g003: Comparison of all-atom root-mean-square deviation and solvent accessible surface areas of Aβ segmental polymorphism models.Backbone Cα atom-positional root-mean-square fluctuations, RMSF, along the amino acid sequence for the five models (A). The results are the average of two independent salutation of each system. The variation of average per residue solvent accessible surface area for each models (B). Red, 16–21P; pink, 16–21AP; blue, 27–32; green, 35–42; yellow, 30–42.
Mentions: We assess the local dynamics and flexibility of the each part of the five segmental polymorphic models of Aβ by calculating the residue-based root mean square fluctuations (RMSF) of the corresponding backbones with respect to their energy minimized structure. Residues in the turn region exhibited a higher flexibility than those in the β-strand regions, except for residues near the N/C-termini (Figure 3A). By visual inspection of the trajectories we find that all 10-mer structures maintain the U turn or “β arch” motif without disassociation of the β-strands. The model based on the 16–21 parallel steric zippers with an NN interface is more stable than the antiparallel counter parts (Figure 3A). This is in agreement with the RMSD result above and with the recent ssNMR experimental study of the Iowa mutant of amyloid β [57]. The model covering 30–40 with longer interface is the most stable polymorph, with smaller fluctuation in both β1 and β2. The terminal amino acids of all structures undergo more dynamic reorientation and are more disordered due to exposure to the solvent molecules (Figure 3A).

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