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Unfolding of the amyloid β-peptide central helix: mechanistic insights from molecular dynamics simulations.

Ito M, Johansson J, Strömberg R, Nilsson L - PLoS ONE (2011)

Bottom Line: WT did not completely unfold in cases when any of the three steps was omitted.MA and ML did not completely unfold mainly due to the lack of the first step.This suggests that disturbances in any of the three steps would be effective in inhibiting the unfolding of the Aβ central helix.

View Article: PubMed Central - PubMed

Affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.

ABSTRACT
Alzheimer's disease (AD) pathogenesis is associated with formation of amyloid fibrils caused by polymerization of the amyloid β-peptide (Aβ), which is a process that requires unfolding of the native helical structure of Aβ. According to recent experimental studies, stabilization of the Aβ central helix is effective in preventing Aβ polymerization into toxic assemblies. To uncover the fundamental mechanism of unfolding of the Aβ central helix, we performed molecular dynamics simulations for wild-type (WT), V18A/F19A/F20A mutant (MA), and V18L/F19L/F20L mutant (ML) models of the Aβ central helix. It was quantitatively demonstrated that the stability of the α-helical conformation of both MA and ML is higher than that of WT, indicating that the α-helical propensity of the three nonpolar residues (18, 19, and 20) is the main factor for the stability of the whole Aβ central helix and that their hydrophobicity plays a secondary role. WT was found to completely unfold by a three-step mechanism: 1) loss of α-helical backbone hydrogen bonds, 2) strong interactions between nonpolar sidechains, and 3) strong interactions between polar sidechains. WT did not completely unfold in cases when any of the three steps was omitted. MA and ML did not completely unfold mainly due to the lack of the first step. This suggests that disturbances in any of the three steps would be effective in inhibiting the unfolding of the Aβ central helix. Our findings would pave the way for design of new drugs to prevent or retard AD.

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Related in: MedlinePlus

Structural and energetic changes of WT+4.The RMSD and Rg (A), the number of αHBs (B), and the backbone O-HN distances of the αHB pairs 1–6 (C) calculated for the middle region (15–24) of the Aβ model are shown. The nonbonded interaction energies including Enp-np (D) and Ep-p (E) are also shown. The structure obtained at 4.28 ns when the number of αHBs starts to decrease, that obtained at 4.59 ns with the Enp-np minimum (−73.58 kcal/mol), and that obtained at 5.29 ns with the notably low Ep-p (−116.13 kcal/mol) are displayed in the black, red, and blue boxes, respectively (F). The structures obtained at 12.72, 16.56, and 19.32 ns with relatively large (9.93 Å), small (6.48 Å), and large (9.65 Å) Rg, respectively, are displayed from the top the bottom in the grey boxes. The initial energy-minimized structure and the structure obtained at 20.00 ns are also displayed at the top and the bottom, respectively. The positions of all the nonpolar residues (thick lines) and those of the polar residues (lines and balls) which are closely located are indicated.
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pone-0017587-g002: Structural and energetic changes of WT+4.The RMSD and Rg (A), the number of αHBs (B), and the backbone O-HN distances of the αHB pairs 1–6 (C) calculated for the middle region (15–24) of the Aβ model are shown. The nonbonded interaction energies including Enp-np (D) and Ep-p (E) are also shown. The structure obtained at 4.28 ns when the number of αHBs starts to decrease, that obtained at 4.59 ns with the Enp-np minimum (−73.58 kcal/mol), and that obtained at 5.29 ns with the notably low Ep-p (−116.13 kcal/mol) are displayed in the black, red, and blue boxes, respectively (F). The structures obtained at 12.72, 16.56, and 19.32 ns with relatively large (9.93 Å), small (6.48 Å), and large (9.65 Å) Rg, respectively, are displayed from the top the bottom in the grey boxes. The initial energy-minimized structure and the structure obtained at 20.00 ns are also displayed at the top and the bottom, respectively. The positions of all the nonpolar residues (thick lines) and those of the polar residues (lines and balls) which are closely located are indicated.

Mentions: In WT+4, a marked increase in RMSD at around 5 ns (from about 1.5 to 5.5 Å) is followed by an increase in Rg at around 12 ns (from about 7 to 9 Å) (Fig. 2A). Since RMSD was calculated for only backbone heavy atoms of the middle region while Rg was calculated for all atoms of the middle region, this shows that the middle region adopts a conformation with a stretched backbone and interacting sidechains from around 5 to 12 ns. After 12 ns, both RMSD and Rg are large, consistent with a fully extended conformation. The complete unfolding thus was triggered at around 5 ns in the WT+4 trajectory, and we inspected the time courses of several variables (number of αHBs, interaction energies between nonpolar (Enp-np) and polar (Ep-p) sidechains) of the trigger point (around 5 ns) to find changes in these variables that were of a larger magnitude than the high-frequency fluctuations.


Unfolding of the amyloid β-peptide central helix: mechanistic insights from molecular dynamics simulations.

Ito M, Johansson J, Strömberg R, Nilsson L - PLoS ONE (2011)

Structural and energetic changes of WT+4.The RMSD and Rg (A), the number of αHBs (B), and the backbone O-HN distances of the αHB pairs 1–6 (C) calculated for the middle region (15–24) of the Aβ model are shown. The nonbonded interaction energies including Enp-np (D) and Ep-p (E) are also shown. The structure obtained at 4.28 ns when the number of αHBs starts to decrease, that obtained at 4.59 ns with the Enp-np minimum (−73.58 kcal/mol), and that obtained at 5.29 ns with the notably low Ep-p (−116.13 kcal/mol) are displayed in the black, red, and blue boxes, respectively (F). The structures obtained at 12.72, 16.56, and 19.32 ns with relatively large (9.93 Å), small (6.48 Å), and large (9.65 Å) Rg, respectively, are displayed from the top the bottom in the grey boxes. The initial energy-minimized structure and the structure obtained at 20.00 ns are also displayed at the top and the bottom, respectively. The positions of all the nonpolar residues (thick lines) and those of the polar residues (lines and balls) which are closely located are indicated.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3049775&req=5

pone-0017587-g002: Structural and energetic changes of WT+4.The RMSD and Rg (A), the number of αHBs (B), and the backbone O-HN distances of the αHB pairs 1–6 (C) calculated for the middle region (15–24) of the Aβ model are shown. The nonbonded interaction energies including Enp-np (D) and Ep-p (E) are also shown. The structure obtained at 4.28 ns when the number of αHBs starts to decrease, that obtained at 4.59 ns with the Enp-np minimum (−73.58 kcal/mol), and that obtained at 5.29 ns with the notably low Ep-p (−116.13 kcal/mol) are displayed in the black, red, and blue boxes, respectively (F). The structures obtained at 12.72, 16.56, and 19.32 ns with relatively large (9.93 Å), small (6.48 Å), and large (9.65 Å) Rg, respectively, are displayed from the top the bottom in the grey boxes. The initial energy-minimized structure and the structure obtained at 20.00 ns are also displayed at the top and the bottom, respectively. The positions of all the nonpolar residues (thick lines) and those of the polar residues (lines and balls) which are closely located are indicated.
Mentions: In WT+4, a marked increase in RMSD at around 5 ns (from about 1.5 to 5.5 Å) is followed by an increase in Rg at around 12 ns (from about 7 to 9 Å) (Fig. 2A). Since RMSD was calculated for only backbone heavy atoms of the middle region while Rg was calculated for all atoms of the middle region, this shows that the middle region adopts a conformation with a stretched backbone and interacting sidechains from around 5 to 12 ns. After 12 ns, both RMSD and Rg are large, consistent with a fully extended conformation. The complete unfolding thus was triggered at around 5 ns in the WT+4 trajectory, and we inspected the time courses of several variables (number of αHBs, interaction energies between nonpolar (Enp-np) and polar (Ep-p) sidechains) of the trigger point (around 5 ns) to find changes in these variables that were of a larger magnitude than the high-frequency fluctuations.

Bottom Line: WT did not completely unfold in cases when any of the three steps was omitted.MA and ML did not completely unfold mainly due to the lack of the first step.This suggests that disturbances in any of the three steps would be effective in inhibiting the unfolding of the Aβ central helix.

View Article: PubMed Central - PubMed

Affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.

ABSTRACT
Alzheimer's disease (AD) pathogenesis is associated with formation of amyloid fibrils caused by polymerization of the amyloid β-peptide (Aβ), which is a process that requires unfolding of the native helical structure of Aβ. According to recent experimental studies, stabilization of the Aβ central helix is effective in preventing Aβ polymerization into toxic assemblies. To uncover the fundamental mechanism of unfolding of the Aβ central helix, we performed molecular dynamics simulations for wild-type (WT), V18A/F19A/F20A mutant (MA), and V18L/F19L/F20L mutant (ML) models of the Aβ central helix. It was quantitatively demonstrated that the stability of the α-helical conformation of both MA and ML is higher than that of WT, indicating that the α-helical propensity of the three nonpolar residues (18, 19, and 20) is the main factor for the stability of the whole Aβ central helix and that their hydrophobicity plays a secondary role. WT was found to completely unfold by a three-step mechanism: 1) loss of α-helical backbone hydrogen bonds, 2) strong interactions between nonpolar sidechains, and 3) strong interactions between polar sidechains. WT did not completely unfold in cases when any of the three steps was omitted. MA and ML did not completely unfold mainly due to the lack of the first step. This suggests that disturbances in any of the three steps would be effective in inhibiting the unfolding of the Aβ central helix. Our findings would pave the way for design of new drugs to prevent or retard AD.

Show MeSH
Related in: MedlinePlus