Interpreting the Mechanism of APOE (p.Leu167del) Mutation in the Incidence of Familial Hypercholesterolemia; An In-silico Approach

Omran Mohammed Rashidi1, #, Fatima Amanullah H.Nazar2, #, Mohamed Nabil Alama3, Zuhier Ahmed Awan1, *
1 Department of Clinical Biochemistry. Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
2 Department of Biology, Genomic and Biotechnology Section. Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
3 Adult interventional cardiology, Cardiology unit, King Abdulaziz University Hospital (KAUH), Jeddah, Saudi Arabia

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Creative Commons License
© 2017 Rashidi et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

* Address correspondence to this author at the Division of Clinical Biochemistry, King Abdulaziz University, Abdullah Sulayman, Jeddah 22254, Saudi Arabia, Tel: +966-12-640-1000# 73717 / 22123; Fax: 640-8451; E-mails:;

# Equal contribution and Shared first authorship



Apolipoprotein E (APOE) gene is a ligand protein in humans which mediates the metabolism of cholesterol by binding to the low-density lipoprotein receptor (LDLR). P.Leu167del mutation in APOE gene was recently connected with Familial Hypercholesterolemia, a condition associated with premature cardiovascular disease. The consequences of this mutation on the protein structure and its receptor binding capacity remain largely unknown.


The current study aims to further decipher the underlying mechanism of this mutation using advanced software-based algorithms. The consequences of disrupting the leucine zipper by this mutation was studied at the structural and functional level of the APOE protein.


3D protein modeling for both APOE and LDLR (wild types), along with APOE (p.Leu167del) mutant type were generated using homology modeling template-based alignment. Structural deviation analysis was performed to evaluate the spatial orientation and the stability of the mutant APOE structure. Molecular docking analysis simulating APOE-LDLR protein interaction was carried out, in order to evaluate the impact of the mutation on the binding affinity.


Structural deviation analysis for APOE mutated model showed low degree of deviance scoring root-mean-square deviation, (RMSD) = 0.322 Å. Whereas Docking simulation revealed an enhanced molecular interaction towards the LDLR with an estimation of +171.03 kJ/mol difference in binding free energy.


This in-silico study suggests that p.Leu167del is causing the protein APOE to associate strongly with its receptor, LDLR. This gain-of-function is likely hindering the ability of LDLR to be effectively recycled back to the surface of the hepatocytes to clear cholesterol from the circulation therefore leading to FH.

Keywords: Apolipoprotein E (APOE), P. Leu167del, Familial Hypercholesterolemia (FH), Homology modeling, Structural deviation, Molecular Docking Simulation.