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. 2013 Dec 18;4(12):1549-58.
doi: 10.1021/cn4001389. Epub 2013 Oct 8.

Arginine and disordered amyloid-β peptide structures: molecular level insights into the toxicity in Alzheimer's disease

Orkid Coskuner  1 , Olivia Wise-Scira
Affiliations

Arginine and disordered amyloid-β peptide structures: molecular level insights into the toxicity in Alzheimer's disease

Orkid Coskuner et al. ACS Chem Neurosci. .

Abstract

Recent studies present that the single arginine (R) residue in the sequence of Aβ42 adopts abundant β-sheet structure and forms stable salt bridges with various residues. Furthermore, experiments proposed that R stimulates the Aβ assembly and arginine (R) to alanine (A) mutation (R5A) decreases both aggregate formation tendency and the degree of its toxicity. However, the exact roles of R and R5A mutation in the structures of Aβ42 are poorly understood. Extensive molecular dynamics simulations along with thermodynamic calculations present that R5A mutation impacts the structures and free energy landscapes of the aqueous Aβ42 peptide. The β-sheet structure almost disappears in the Ala21-Ala30 region but is more abundant in parts of the central hydrophobic core and C-terminal regions of Aβ42 upon R5A mutation. More abundant α-helix is adopted in parts of the N-terminal and mid-domain regions and less prominent α-helix formation occurs in the central hydrophobic core region of Aβ42 upon R5A mutation. Interestingly, intramolecular interactions between N- and C-terminal or mid-domain regions disappear upon R5A mutation. The structures of Aβ42 are thermodynamically less stable and retain reduced compactness upon R5A mutation. R5A mutant-type structure stability increases with more prominent central hydrophobic core and mid-domain or C-terminal region interactions. Based on our results reported in this work, small organic molecules and antibodies that avoid β-sheet formation in the Ala21-Ala30 region and hinder the intramolecular interactions occurring between the N-terminal and mid-domain or C-terminal regions of Aβ42 may help to reduce Aβ42 toxicity in Alzheimer's disease.

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Figures

Figure 1
Figure 1
Wild-type and R5A mutant-type Aβ42 secondary structure components. Secondary structures along with their abundances per residue for the wild-type (black) and R5A mutant-type (red) Aβ42 peptides per residue. The abundances for the π-helix and coil structures are not displayed.
Figure 2
Figure 2
Secondary structure transition stabilities per residue of the wild-type and R5A mutant-type Aβ42 peptides. The stability of secondary structure transitions between two specific secondary structure components per residue for the wild-type (A) and R5A mutant-type (B) Aβ42 peptides in aqueous solution. The color scale corresponds to the free energy value associated with specific transitions between two secondary structure components for a specific residue.
Figure 3
Figure 3
WT and R5A mutant-type Aβ42 PMF surfaces. Change in the potential of mean force (ΔPMF) of the wild-type (A) and R5A mutant-type (B) Aβ42 peptides along the coordinates of radius of gyrations (Rg) and end-to-end distance (RE-E) in units of kJ mol–1. Representative structures of the most preferred PMF basins (basin IA and basin IB for the WT and basin I for the R5A mutant-type Aβ peptides) are displayed next to each PMF surface. The secondary structure components per residue for each structure are correlated with the color of the peptide backbone as follows: α-helix (blue), 310-helix (gray), π-helix (purple), β-sheet (red), β-bridge (black), turn (yellow), and coil (white).
Figure 4
Figure 4
Wild-type and R5A mutant-type Aβ42 tertiary structures. Intramolecular interactions and abundances in the structures of the wild-type (A) and the R5A mutant-type (B) Aβ42 peptides. The color scale corresponds to the probability (P) of the distance between the centers of mass between two residues being ≤9 Å from each other.
Figure 5
Figure 5
Intramolecular interactions in the structures of the wild-type Aβ42 peptide located in basin I (A.1), basin II (A.2), and basin III (A.3) and in the structures of the R5A mutant-type Aβ42 located in basin I (B.1), basin II (B.2), and basin III (B.3) of the PMF surfaces. The color scale corresponds to the probability (P) of the distance between the centers of mass between two residues being ≤9 Å from each other.
Figure 6
Figure 6
The calculated probability distribution of the distance between the Cγ atom of the E22 (A) or D23 (B) residues and the Nζ atom of the K28 residue for all converged structures of the wild-type (black) and R5A mutant-type (red) Aβ42 peptides.
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