Figure 1.
Computational docking and molecular dynamics for ApoE and Aβ.
(A) Comparison of the crystal structures of the N-terminal domain of the different ApoE truncated isoforms. The α-carbons of the different ApoE isoform crystal structures were aligned and plotted as ribbons. Residues 112 and 158, which variability leads to the different isoforms have been plotted as ball and sticks. For a clearer representation, the most representative areas of the protein have been scaled in the insets. The atoms of the corresponding side chains have been colored using the following color code: red for ApoE2, green for ApoE3 and orange for ApoE4. Arg61 has been also plotted using the same representation mode and color code. (B) Docking of Apolipoprotein E with Aβ peptide. Isoforms E2, E3 and E4 models with lowest global energy docked with the Aβ peptide are represented. The surface corresponding to the occupancy of both ApoE and Aβ is represented in white. ApoE and Aβ are represented by blue and golden cartoons, respectively. Residues 61, 112 and 158 have been represented as ball and sticks and colored by element (C, grey; S, yellow; N, blue). (C) RMSDs for ApoE and Aβ peptide by molecular dynamics with GROMACS. (ApoE) RMSD values of the dynamics for ApoE complexed or not with Aβ peptide. ApoE alone: ApoE2, black; ApoE3, red; ApoE4, green. ApoE-Aβ complex: ApoE2- Aβ, blue; ApoE3- Aβ, purple; ApoE4-Aβ, grey. (Aβ) RMSD values of the dynamics for the Aβ peptide complexed with ApoE: ApoE2- Aβ, black; ApoE3- Aβ, red; ApoE4- Aβ, grey. (D) Snapshots from the ApoE4-Aβ complex formation during the MD simulation. Plot of the folding intermediates generated by the MD simulation at the indicated times. ApoE and Aβ are represented by blue and golden surfaces/cartoons, respectively. It is noteworthy the loss of secondary structure as a function of time.
Figure 2.
Distance analysis between Aβ and ApoE residues involved in the electrostatic interactions during the ApoE-Aβ complex formation.
The structure plotted corresponds to the ApoE4-Aβ complex (color code blue and golden, respectively). Aβ residues are indicated by underlined and italics characters. Aβ peptide residues from Gly25 to Val40 have been removed for a clearer representation. The sub index for the ApoE4 residues indicates helix location. The green dotted line depicts the salt bridge network between residues of the Aβ peptide and ApoE4 and between residues in the ApoE4 helices I and II. (A) Distance variation during the 10 ns MD simulation for the Aβ Asp23 and the ApoE4 Arg38 electrostatic pair (black) and the Aβ Asp1 and the ApoE4 Arg142 electrostatic pair (grey). (B) Distance variation during the 10 ns MD simulation for the Asp35-Arg38 electrostatic pair, for ApoE4 alone (grey) and for ApoE4-Aβ (black). (C) Distance variation during the 10 ns MD simulation for the Arg32-Asp35 electrostatic pair, for ApoE4 alone (grey) and for ApoE4-Aβ (black). (D) Distance variation during the 10 ns MD simulation for the Arg32-Glu66 electrostatic pair, for ApoE4 alone (grey) and for ApoE4-Aβ (black). In all plots the salt bridge thresholds of 4.3 and 7.0 Å are indicated by dashed lines. Selected residues have been represented as ball and sticks and colored by element (C, grey; O, red; N, blue).
Figure 3.
Distance analysis between ApoE residues involved in the electrostatic interactions between helices II and III of the N-terminal domain during the ApoE-Aβ complex formation.
The structure plotted corresponds to the ApoE4-Aβ complex (color code blue and golden, respectively). The sub index for the ApoE4 residues indicates helix location. The green dotted line depicts the salt bridge network between residues in the ApoE4 helices II and III. (A) Distance variation during the 10 ns MD simulation for the Arg61-Glu66 electrostatic pair, for ApoE4 alone (grey) and for ApoE4-Aβ (black). (B) Distance variation during the 10 ns MD simulation for the Arg61-Glu109 electrostatic pair, for ApoE4 alone (grey) and for ApoE4-Aβ (black). (C) Distance variation during the 10 ns MD simulation for the Arg112-Glu109 electrostatic pair, for ApoE4 alone (grey) and for ApoE4-Aβ (black). (D) Distance variation during the 10 ns MD simulation for the Arg112-Asp110 electrostatic pair, for ApoE4 alone (grey) and for ApoE4-Aβ (black). In all plots the salt bridge thresholds of 4.3 and 7.0 Å are indicated by dashed lines. Selected residues have been represented as ball and sticks and colored by element (C, grey; O, red; N, blue).
Figure 4.
Proposed model for the Aβ peptide and ApoE4 interaction.
The interaction of Aβ with ApoE4 rearranges the salt bridge network. This is the overall representation of the interaction effect between the peptide and the protein. (Upper panel) 3D plot of the ApoE4-Aβ complex (colored blue and golden respectively) depicting the rearranged salt bridge network (green dotted lines). Selected residues have been represented as ball and sticks and colored by element (C, grey; O, red; N, blue). (Lower panel) 2D scheme for a clearer understanding of the rearranged salt bridge network. The sub index for the ApoE4 residues indicates helix location. Aβ residues into grey shaded boxes are indicated by underlined and italics characters.