Table 1.
Overview of Computational Tools Used for Predicting Deleterious nsSNPs, Including Their Analytical Approaches, Input Parameters, and Accuracy Rate.
Fig 1.
Schematic representation of the methodological approach.
Fig 2.
Data integration and identification of deleterious nsSNPs in the ApoE gene.
A) Venn diagram illustrating the overlap of non-synonymous SNPs (nsSNPs) retrieved from three databases. B) A bar chart displays the number of nsSNPs identified by eight [8] different computational tools. C) A Venn diagram highlights ten nsSNPs classified as the most deleterious, as they were consistently predicted to be harmful by all eight tools.
Table 2.
Common deleterious nsSNPs [10] identified by eight in-silico prediction tools.
Table 3.
Stability and structural analysis of ApoE protein caused by 10 common nsSNPs.
Fig 3.
Structural alterations and hydrogen bonding patterns induced by mutations in the ApoE protein, visualized using Swiss PDB Viewer.
L107P mutation: The wild-type residue forms four hydrogen bonds, while the mutant residue forms only two. L122P mutation: The wild-type residue establishes three hydrogen bonds, reduced to two in the mutant, disrupting local structural stability. A208P mutation: The wild-type residue forms one hydrogen bond, while the mutant residue forms no bond. The 3D representations illustrate the wild-type (green) and mutant (red) residues and their respective hydrogen bond networks (indicated by green dashed lines).
Fig 4.
Selection of high-risk [2] nsSNPs rs1238105907 (L122P) and rs1969853804 (L107P) utilizing computational tools.
Using computational tools, we identified two high-risk genetic variants—rs1238105907 (L122P) and rs1969853804 (L107P)—that are likely to affect both the stability and structure of the protein.
Fig 5.
Domain identification of ApoE protein using InterPro server.
It predicted the receptor binding domain (1-167), lipid binding domain (206-299) and hinge region (168-205) of ApoE.
Fig 6.
Prediction of protein–protein interactions (PPI) using STRING v.
11.0 and Cytoscape. (A) Protein–protein interaction network of ApoE (yellow node) with key proteins involved in lipid metabolism and Alzheimer’s disease, including CLU, LRP8, APOB, LRP1, and APP. These interactions are crucial for processes like amyloid beta (Aβ) clearance, lipid transport, and neuroinflammation in AD. (B) Confidence scores of the interactions indicating the reliability of these connections based on experimental and computational data.
Table 4.
Structural Validation of Wild-Type and High-Risk ApoE Mutant Protein Models.
Fig 7.
Structural comparison of the active sites in wild-type and mutant ApoE protein models generated by the CASTpFold server.
The ribbon diagrams show the structure of ApoE in four forms: (A) the WT version with Leucine at position 122, (B) the mutated version with Proline at position 122, (C) the WT version with Leucine at position 107, and (D) the mutated version with Proline at position 107. In each model, the red spherical surface marks the active site’s surface area.
Table 5.
Binding affinities and contact residues of WT and mutant ApoE protein with Aβ.
Fig 8.
Illustrates the molecular docking results comparing the interactions of native ApoE and the mutant ApoE (L122P) with Aβ.
Panel (A) depicts the 3D and 2D interaction of WT ApoE bound to Aβ. In the right-hand corner, the stick structure represents Aβ interacting with the active site residue of WT ApoE. (B) highlights the 3D and 2D interaction between the mutant ApoE (L122P) and Aβ. In the right-hand down corner, the stick structure represents Aβ interacting with the active site residue of mutant ApoE (L122P).
Fig 9.
Molecular dynamics simulation of WT and Mutant ApoE–Aβ complexes with a 100 ns runtime.
A) Root Mean Square Deviation (RMSD); B) Root Mean Square Fluctuation (RMSF); C) Radius of Gyration (Rg); and D) Solvent accessible surface area (SASA).
Fig 10.
Protein-ligand interaction profiles during molecular dynamics (MD) simulations.
A) WT_Aβ; B) L107P_Aβ; C) L122P_Aβ. The stacked bar charts represent the fraction of different interaction types between the ligand and residues of the protein across the MD trajectories: hydrogen bonds (green), hydrophobic interactions (purple), ionic interactions (magenta), and water bridges (blue).