In Silico Analysis of the Apolipoprotein E and the Amyloid β Peptide Interaction: Misfolding Induced by Frustration of the Salt Bridge Network
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.